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Sultan MH, Zhan Q, Wang Y, Xia Y, Jia X. Precision oncolytic viral therapy in colorectal cancer: Genetic targeting and immune modulation for personalized treatment (Review). Int J Mol Med 2025; 56:104. [PMID: 40342021 PMCID: PMC12081034 DOI: 10.3892/ijmm.2025.5545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/09/2025] [Indexed: 05/11/2025] Open
Abstract
Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.
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Affiliation(s)
- Muhammad Haris Sultan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Qi Zhan
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yigang Wang
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
| | - Yulong Xia
- Center for Translational Medicine and Precision Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoyuan Jia
- College of Life Sciences and Medicine, Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China
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2
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Pizzamiglio M, Soulabaille A, Lahlou W, Pilla L, Zaanan A, Taieb J. Advances and challenges in targeted therapies for HER2-amplified colorectal cancer. Eur J Cancer 2025; 222:115471. [PMID: 40311507 DOI: 10.1016/j.ejca.2025.115471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 05/03/2025]
Abstract
Colorectal cancer is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. Despite an increase in overall survival throughout the years, the prognosis of metastatic colorectal cancer remains poor. Until recently, its treatment was based on the use of standard chemotherapy combined with, anti-epidermal growth factor receptor (for RAS wild-type tumors) or anti-vascular endothelial growth factor, or immunotherapy for tumors with mismatch repair deficiency. Over the last years, precision medicine has become a challenge in oncology and there has been an increasing development of biomarker-driven therapies for metastatic colorectal cancer leading to better outcomes for specific molecular subgroups of patients. Human epidermal growth factor receptor 2 (HER2) amplification/overexpression has been identified in about 6 % of patients with RAS wild-type metastatic CRC and established as an important and drugable biomarker. Its prognostic and predictive implications are still debated but HER2 becoming a therapeutic target with promising results of anti-HER2 therapies for HER2-positive metastatic CRC. Multiple HER2-targeted regimens are now part of National Comprehensive Cancer Network and European Society for Medical Oncology guidelines with two recent Food and Drug Administration approvals for previously treated HER2-positive metastatic colorectal cancer for tucatinib (in combination with trastuzumab) and for trastuzumab-deruxtecan in patients with previously treated HER2-positive metastatic colorectal cancer. This review explores the prognostic and predictive value of HER2 as a biomarker in CRC, describing its molecular structure, the clinical characteristics of patients with HER2 alterations, diagnostic approaches and the most relevant clinical trials assessing its current and future role as a therapeutic target in metastatic colorectal cancer.
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Affiliation(s)
- Margot Pizzamiglio
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Audrey Soulabaille
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Widad Lahlou
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Lorenzo Pilla
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Aziz Zaanan
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France
| | - Julien Taieb
- Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Department of Digestive Oncology, Hôpital européen Georges Pompidou, Paris, France.
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Hwang SY, Seo Y, Park S, Kim SA, Moon I, Liu Y, Kim S, Pak ES, Jung S, Kim H, Jeon KH, Seo SH, Sung I, Lee H, Park SY, Na Y, Kim TI, Kwon Y. Targeting the HER2-ELF3-KRAS axis: a novel therapeutic strategy for KRAS G13D colorectal cancer. Mol Cancer 2025; 24:139. [PMID: 40340861 PMCID: PMC12063335 DOI: 10.1186/s12943-025-02343-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 04/25/2025] [Indexed: 05/10/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, with KRAS mutations playing a significant role in its tumorigenesis. Among the KRAS variants, the G13D mutation is associated with poor prognosis and distinctive biological behaviors. This study focuses on the role of HER2, a critical prognostic and predictive biomarker, in modulating the unique characteristics of KRASG13D-mutated CRCs. We identified a novel transcriptional regulatory network involving HER2, ELF3, and KRAS, with ELF3 acting as a key transcription factor (TF) that regulates KRAS expression under conditions of HER2 overexpression. Our findings reveal that this HER2-ELF3-KRAS axis is exclusively activated in KRASG13D, driving aggressive oncogenic features and conferring resistance to cetuximab (CTX) therapy. Through comprehensive analysis of gene expression profiles, we demonstrated that HER2 is a crucial therapeutic target specifically for KRASG13D CRCs. To explore this further, we introduced YK1, a small molecule inhibitor designed to disrupt the ELF3-MED23 interaction, leading to the transcriptional downregulation of HER2 and KRAS. This intervention significantly attenuated the HER2-ELF3-KRAS axis, sensitizing KRASG13D CRCs to CTX and reducing their tumorigenic potential by inhibiting the epithelial-to-mesenchymal transition process. Our study underscores the importance of HER2 as a key determinant in the unique biological characteristics of KRASG13D CRCs and highlights the therapeutic potential of targeting the HER2-ELF3-KRAS axis. By presenting YK1 as a novel pharmacological approach, we provide a promising strategy for developing tailored interventions for KRASG13D CRCs, contributing to the ongoing efforts in precision medicine for CRCs.
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Affiliation(s)
- Soo-Yeon Hwang
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Yoojeong Seo
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-Gu, Seoul, 03722, Republic of Korea
| | - Seojeong Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seul-Ah Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
- Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Inhye Moon
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
- Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Yi Liu
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seojeong Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Eun Seon Pak
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Sehyun Jung
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Hyeyoon Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Kyung-Hwa Jeon
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seung Hee Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Inyoung Sung
- BK21 FOUR Intelligence Computing, Seoul National University, Seoul, Republic of Korea
| | - Heetak Lee
- Center for Genome Engineering, Institute for Basic Science, 55, Expo-Ro, Yuseong-Gu, Daejeon, 34126, Republic of Korea
| | - So-Yeon Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Younghwa Na
- College of Pharmacy, CHA University, Pocheon, 11160, Republic of Korea
| | - Tae Il Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-Gu, Seoul, 03722, Republic of Korea
| | - Youngjoo Kwon
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
- Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea.
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Appleyard JW, Williams CJM, Manca P, Pietrantonio F, Seligmann JF. Targeting the MAP kinase pathway in colorectal cancer: A journey in personalized medicine. Clin Cancer Res 2025:762187. [PMID: 40310309 PMCID: PMC7617663 DOI: 10.1158/1078-0432.ccr-25-0107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/25/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025]
Abstract
The anti-EGFR agents, cetuximab and panitumumab, were the first targeted agents to be licensed in colorectal cancer and marked a significant advancement in personalized care. Initial biomarkers provided poor discrimination between responders and non-responders. Through hypothesis-led translational studies, tumor genomic negative predictive markers were identified, and treatment is now limited to patients with RAS and BRAF wild-type disease. Guidelines further recommend treatment limitation to those with left-primary tumor location (PTL). Despite such progress, anti-EGFR response remains variable within the biomarker-selected population, indicating the presence of additional mechanisms of resistance and underscoring the need for novel positive predictive biomarkers, and novel targeted agents. This review explores established and emerging predictive biomarkers of anti-EGFR efficacy, including tumor genetic alterations beyond RAS and BRAF, as well as the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG). To date, biomarker discovery and validation have largely been performed within post hoc analyses of existing clinical trial datasets. We highlight ongoing prospective clinical trials aiming to validate earlier findings and describe how novel biomarkers are being used to re-evaluate anti-EGFR agents in treatment settings where earlier trials, among non-biomarker selected populations, yielded negative results - including right-PTL, locally advanced disease, and anti-EGFR rechallenge strategies. Additionally, we discuss how our improved understanding of the molecular mechanisms underpinning anti-EGFR response and resistance is being leveraged to develop novel targeted agents.
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Affiliation(s)
- Jordan W. Appleyard
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds, United Kingdom
| | | | - Paolo Manca
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Jenny F. Seligmann
- Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds, United Kingdom
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Garrett JT, Tendler S, Feroz W, Kilroy MK, Yu H. Emerging importance of HER3 in tumorigenesis and cancer therapy. Nat Rev Clin Oncol 2025; 22:348-370. [PMID: 40087402 DOI: 10.1038/s41571-025-01008-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2025] [Indexed: 03/17/2025]
Abstract
HER3 is a member of the HER/ErbB family of receptor tyrosine kinases, together with EGFR (HER1), HER2 and HER4. Despite having only weak intrinsic kinase activity, HER3 can contribute to oncogenic signalling via ligand-induced heterodimerization with other HER family members. Evidence indicates that HER3 is altered or aberrantly expressed across a variety of tumour types and can be associated with poor clinical outcomes. Whereas anticancer agents targeting EGFR and HER2 have been approved for decades, no drug targeting HER3 had been approved until very recently. Initial targeting of HER3 with monoclonal antibodies as single agents or in combination with other therapeutics produced disappointing clinical results. Subsequently, efforts have been made to target HER3 with novel agents such as antibody-drug conjugates and bispecific antibodies, with promising efficacy observed in several trials encompassing various tumour types. In December 2024, the HER3 × HER2 bispecific antibody zenocutuzumab was granted FDA Accelerated Approval for the treatment of non-small-cell lung cancers or pancreatic cancers harbouring fusions involving NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1. In this Review, we provide an essential guide to HER3 signalling and oncogenesis, HER3 expression in cancer and its prognostic implications, oncogenic HER3 somatic mutations as well as rare NRG1 fusions that might depend on HER3 signalling, and the roles of HER3 in resistance to cancer therapies. We also highlight efforts to target HER3 with diverse therapeutic strategies and the potential interplay between HER3 and the antitumour immune response.
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Affiliation(s)
- Joan T Garrett
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
| | - Salomon Tendler
- Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wasim Feroz
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
| | - Mary Kate Kilroy
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
| | - Helena Yu
- Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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6
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Xiao X, Wang QW, Zhou ZY, Wang LS, Huang P. Precision treatment for human epidermal growth factor receptor 2-amplified advanced rectal cancer: A case report. World J Gastrointest Oncol 2025; 17:102690. [PMID: 40235909 PMCID: PMC11995321 DOI: 10.4251/wjgo.v17.i4.102690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/23/2025] [Accepted: 02/17/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer, some patients develop resistance to these treatments. Human epidermal growth factor receptor 2 (HER2) is overexpressed in a subset of patients with colorectal cancer and has been established as a therapeutic target. CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors (ICIs) in combination with pyrotinib. The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression. CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer. Chemotherapy following disease progression could enhance efficacy synergistically.
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Affiliation(s)
- Xia Xiao
- Department of Oncology, Wuxi No. 2 People’s Hospital, Jiangnan University Medical Center, Wuxi 214002, Jiangsu Province, China
| | - Qing-Wen Wang
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Zheng-Yang Zhou
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Lei-Sheng Wang
- Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
| | - Pei Huang
- Department of Oncology, Wuxi No. 2 People’s Hospital, Jiangnan University Medical Center, Wuxi 214002, Jiangsu Province, China
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Huang H, Zhou Y, Shang C, Zhang Y, Shen Y. A novel anti-HER2/EGFR bispecific antibody-drug conjugate demonstrates promising antitumor efficacy and overcomes resistance to HER2- or EGFR-targeted ADCs. Invest New Drugs 2025; 43:262-275. [PMID: 39982632 DOI: 10.1007/s10637-025-01507-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 01/17/2025] [Indexed: 02/22/2025]
Abstract
HER2 and EGFR are frequently co-expressed in various tumors. While antibody-drug conjugates (ADCs) targeting HER2, such as T-DM1 and T-Dxd, have shown remarkable antitumor effects in clinical responses, their effectiveness is constrained by drug resistance. EGFR amplification or high expression is one of the factors that lead to resistance against HER2-targeted ADCs. Likewise, the amplification of HER2 may lead to the development of resistance to EGFR-targeted therapies. To overcome these challenges, we, therefore, developed a bispecific antibody (B2C4) that targets HER2 and EGFR. B2C4 exhibited strong binding affinity and internalization activity in tumor cells with high expression of HER2 and EGFR, as well as in those with high expression of either target. B2C4 was then conjugated with vc-MMAE to create a bispecific ADC (B2C4-MMAE) with an average DAR of 4.05. By effectively engaging both arms of the bispecific ADC, B2C4-MMAE demonstrated significant antitumor activity in tumor cells and animal models that were unresponsive HER2- or EGFR-targeted ADCs. B2C4-MMAE could serve as an alternative therapeutic option for tumors that are resistant to single-target treatments. Additionally, B2C4-MMAE exhibited potential in treating tumors resistant to T-Dxd, underscoring its promise as a treatment for challenging cases.
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Affiliation(s)
- Huoying Huang
- Anhui University of Chinese Medicine, Hefei, People's Republic of China
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co., Ltd, Beijing, People's Republic of China
- Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong, People's Republic of China
| | - Yuxin Zhou
- Anhui University of Chinese Medicine, Hefei, People's Republic of China
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co., Ltd, Beijing, People's Republic of China
- Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong, People's Republic of China
| | - Chengzhang Shang
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co., Ltd, Beijing, People's Republic of China
| | - Yifu Zhang
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co., Ltd, Beijing, People's Republic of China
| | - Yuelei Shen
- Institute of Innovative Medicine, Biocytogen Pharmaceuticals (Beijing) Co., Ltd, Beijing, People's Republic of China.
- Joint Graduate School, Yangtze Delta Drug Advanced Research Institute, Nantong, People's Republic of China.
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Hoyek C, Zheng-Lin B, Jones J, Bekaii-Saab T. Tucatinib in the treatment of HER2-overexpressing gastrointestinal cancers: current insights and future prospects. Expert Opin Investig Drugs 2025; 34:161-168. [PMID: 40019490 DOI: 10.1080/13543784.2025.2472411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 02/23/2025] [Indexed: 03/01/2025]
Abstract
INTRODUCTION Over the past 20 years, the treatment landscape of HER2-amplified tumors has considerably evolved. Until now, no approved targeted therapies were available for patients with HER2-amplified metastatic colorectal cancer (mCRC). Tucatinib, a highly selective tyrosine kinase inhibitor, demonstrated significant efficacy in combination with trastuzumab in patients with refractory mCRC, leading to its approval by the Food and Drug Administration (FDA). AREAS COVERED This review dives into the efficacy of tucatinib-based regimens in gastrointestinal malignancies, with a focus on the pivotal MOUNTAINEER trial, which led to the FDA approval of tucatinib plus trastuzumab in chemo-refractory HER2-amplified mCRC. Additionally, ongoing trials are exploring tucatinib in earlier treatment lines and across other gastrointestinal cancers, including biliary tract, gastric, and pancreatic malignancies. The mechanistic basis of dual HER2 inhibition and its implications for clinical practice are discussed. EXPERT COMMENTARY The future of tucatinib-based therapeutic strategies in GI malignancies depends on their integration into different treatment lines. Addressing acquired resistance using liquid biopsy-guided strategies and other TKIs like lapatinib will be paramount to improve outcomes.
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Affiliation(s)
- Celine Hoyek
- Department of Hematology and Oncology, Mayo Clinic, Arizona, AZ, USA
| | - Binbin Zheng-Lin
- Department of Hematology and Oncology, Mayo Clinic, Arizona, AZ, USA
| | - Jeremy Jones
- Department of Hematology and Oncology, Mayo Clinic, Florida, FL, USA
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Vonica RC, Morgovan C, Butuca A, Pumnea M, Cipaian RC, Frum A, Dobrea CM, Vonica-Tincu AL, Pacnejer AM, Batar F, Vornicu V, Ghibu S, Gligor FG. Real-World Evidence of Bevacizumab and Panitumumab Drug Resistance and Drug Ineffectiveness from EudraVigilance Database. Cancers (Basel) 2025; 17:663. [PMID: 40002260 PMCID: PMC11853327 DOI: 10.3390/cancers17040663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/02/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world, with an average 5-year overall survival (OS) rate of approximately 60% [...].
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Affiliation(s)
- Razvan Constantin Vonica
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Manuela Pumnea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Remus Calin Cipaian
- Clinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania;
- County Clinical Emergency Hospital of Sibiu, 2-4 Corneliu Coposu Str., 550245 Sibiu, Romania
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Andreea Loredana Vonica-Tincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Aliteia-Maria Pacnejer
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
- Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Florina Batar
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Vlad Vornicu
- Department IX Surgery, Discipline of Oncology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania;
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
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10
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Ji P, Chen T, Li C, Zhang J, Li X, Zhu H. Comprehensive review of signaling pathways and therapeutic targets in gastrointestinal cancers. Crit Rev Oncol Hematol 2025; 206:104586. [PMID: 39653094 DOI: 10.1016/j.critrevonc.2024.104586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024] Open
Abstract
Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.
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Affiliation(s)
- Pengfei Ji
- Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China
| | - Tingting Chen
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Chao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Jinyuan Zhang
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Xiao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China.
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11
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Lee J, Song J, Yoo W, Choi H, Jung D, Choi E, Jo SG, Gong EY, Jeoung YH, Park YS, Son WC, Lee H, Lee H, Kim JJ, Kim T, Lee S, Park JJ, Kim TD, Kim SH. Therapeutic potential of anti-ErbB3 chimeric antigen receptor natural killer cells against breast cancer. Cancer Immunol Immunother 2025; 74:73. [PMID: 39751931 PMCID: PMC11698710 DOI: 10.1007/s00262-024-03923-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/13/2024] [Indexed: 01/04/2025]
Abstract
ErbB3 is markedly overexpressed in breast cancer cells and is associated with resistance and metastasis. Additionally, ErbB3 expression levels are positively correlated with low densities of tumor-infiltrating lymphocytes, a marker of poor prognosis. Consequently, ErbB3 is a promising therapeutic target for cancer immunotherapy. Here, we report the generation of ErbB3-targeted chimeric antigen receptor (CAR)-modified natural killer (NK) cells by transducing cord blood-derived primary NK cells using vsv-g envelope-pseudotyped lentiviral vectors. Transduced cells displayed stable CAR-expressing activity and increased cytotoxicity against ErbB3-positive breast cancer cell lines. Furthermore, anti-ErbB3 (aErbB3) CAR-NK cells strongly reduced the tumor burden in the SK-BR-3 xenograft mouse model without observable side effects. These findings underscore the potential of aErbB3 CAR-NK cells as targeted immunotherapy for ErbB3-positive breast cancer, suggesting a promising alternative to conventional treatments.
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Affiliation(s)
- Juheon Lee
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Jinhoo Song
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Wonbeak Yoo
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Hyunji Choi
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Dana Jung
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Eunjeong Choi
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Seo-Gyeong Jo
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea
| | - Eun-Yeung Gong
- Department of Medicinal Biotechnology, College of Health Science, Dong-A University, Busan, 49315, Republic of Korea
| | - Young-Hee Jeoung
- Department of Medicinal Biotechnology, College of Health Science, Dong-A University, Busan, 49315, Republic of Korea
| | - You-Soo Park
- Department of Research Center, Dongnam Institute of Radiological and Medical Sciences Busan, Busan, 46033, Republic of Korea
| | - Woo-Chang Son
- Department of Research Center, Dongnam Institute of Radiological and Medical Sciences Busan, Busan, 46033, Republic of Korea
| | - Hosuk Lee
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Hayoung Lee
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Jeom Ji Kim
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - TaeEun Kim
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Sooyun Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Jang-June Park
- ISU Abxis, Drug Discovery Division, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
| | - Seok-Ho Kim
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea.
- Department of Medicinal Biotechnology, College of Health Science, Dong-A University, Busan, 49315, Republic of Korea.
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12
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Ciracì P, Studiale V, Taravella A, Antoniotti C, Cremolini C. Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm. Nat Rev Clin Oncol 2025; 22:28-45. [PMID: 39558030 DOI: 10.1038/s41571-024-00965-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 11/20/2024]
Abstract
Over the past few years, several novel systemic treatments have emerged for patients with treatment-refractory metastatic colorectal cancer, thus making selection of the most effective later-line therapy a challenge for medical oncologists. Over the past decade, regorafenib and trifluridine-tipiracil were the only available drugs and often provided limited clinical benefit compared to best supportive care. Results from subsequent practice-changing trials opened several novel therapeutic avenues, both for unselected patients (such as trifluridine-tipiracil plus bevacizumab or fruquintinib) and for subgroups defined by the presence of actionable alterations in their tumours (such as HER2-targeted therapies or KRASG12C inhibitors) or with no acquired mechanisms of resistance to the previously received targeted agents in circulating tumour DNA (such as retreatment with anti-EGFR antibodies). In this Review, we provide a comprehensive overview of advances in the field over the past few years and offer a practical perspective on translation of the most relevant results into the daily management of patients with metastatic colorectal cancer using an evidence-based algorithm. Finally, we discuss some of the most appealing ongoing areas of research and highlight approaches with the potential to further expand the therapeutic armamentarium.
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Affiliation(s)
- Paolo Ciracì
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Vittorio Studiale
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Ada Taravella
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Carlotta Antoniotti
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Chiara Cremolini
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
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13
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Berner AM, Murugaesu N. The Evolving Role of Genomics in Colorectal Cancer. Clin Oncol (R Coll Radiol) 2025; 37:103661. [PMID: 39536702 DOI: 10.1016/j.clon.2024.10.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 08/08/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
Approximately 75% of colorectal cancers (CRCs) harbour an identifiable driver mutation, 5% of which are heritable. These drivers have recognised implications for prognosis and therapy selection. In addition, potential germline mutations require investigations to inform testing of relatives, as well as surveillance for other malignancies. With increasing numbers of targeted drugs being approved, judicious testing is required to ensure sufficient tumour sample is available for testing and at the right point in the cancer pathway. Liquid biopsy with circulating tumour DNA (ctDNA) in the blood presents an exciting adjunct to tumour tissue testing for molecular drivers, as well as escalation and de-escalation of therapy. Here, we review the most frequent molecular alterations in CRC, how genomic testing should be integrated into the treatment pathway for CRC, and sources of further education.
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Affiliation(s)
- A M Berner
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6AU, UK
| | - N Murugaesu
- Guy's & St Thomas' NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK; Genomics England, 1 Canada Square, London E14 5AB, UK.
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14
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Venturini J, Massaro G, Lavacchi D, Rossini D, Pillozzi S, Caliman E, Pellegrini E, Antonuzzo L. The emerging HER2 landscape in colorectal cancer: the key to unveil the future treatment algorithm? Crit Rev Oncol Hematol 2024; 204:104515. [PMID: 39304034 DOI: 10.1016/j.critrevonc.2024.104515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024] Open
Abstract
Colorectal cancer (CRC) represents a global health threat, standing as the second leading cause of cancer-related death worldwide. Targeted therapies brought new hope for the metastatic stage, which historically bore a very poor prognosis. Human epidermal growth receptor 2 (HER2) overexpression concerns about 5 % of the metastatic CRC (mCRC) patients, including both gene amplifications and point mutations. Albeit its controversial prognostic role, preclinical and clinical data indicate HER2 as a negative predictive biomarker of response to anti-EGFR therapies. Tissue and plasma-based NGS testing, could permit a precise identification of this resistance mechanism both at baseline and during treatment, thus guiding decision-making. Furthermore, promising results come from completed and ongoing randomized trials, testing HER2 as an actionable target. In this review, we discuss the available evidence on HER2 targeting in advanced CRC, analyzing its possible future role in the treatment algorithm.
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Affiliation(s)
- Jacopo Venturini
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Giulia Massaro
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Daniele Lavacchi
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Daniele Rossini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy; Department of Health Science, University of Florence, Florence 50139, Italy
| | - Serena Pillozzi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy; Medical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Enrico Caliman
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Elisa Pellegrini
- Medical Oncology Unit, Careggi University Hospital, Florence 50134, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence 50134, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy; Medical Oncology Unit, Careggi University Hospital, Florence 50134, Italy.
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15
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Perron U, Grassi E, Chatzipli A, Viviani M, Karakoc E, Trastulla L, Brochier LM, Isella C, Zanella ER, Klett H, Molineris I, Schueler J, Esteller M, Medico E, Conte N, McDermott U, Trusolino L, Bertotti A, Iorio F. Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts. Nat Commun 2024; 15:9139. [PMID: 39528460 PMCID: PMC11555063 DOI: 10.1038/s41467-024-53163-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
Patient-derived xenografts (PDXs) are tumour fragments engrafted into mice for preclinical studies. PDXs offer clear advantages over simpler in vitro cancer models - such as cancer cell lines (CCLs) and organoids - in terms of structural complexity, heterogeneity, and stromal interactions. Here, we characterise 231 colorectal cancer PDXs at the genomic, transcriptomic, and epigenetic levels, along with their response to cetuximab, an EGFR inhibitor used clinically for metastatic colorectal cancer. After evaluating the PDXs' quality, stability, and molecular concordance with publicly available patient cohorts, we present results from training, interpreting, and validating the integrative ensemble classifier CeSta. This model takes in input the PDXs' multi-omic characterisation and predicts their sensitivity to cetuximab treatment, achieving an area under the receiver operating characteristics curve > 0.88. Our study demonstrates that large PDX collections can be leveraged to train accurate, interpretable drug sensitivity models that: (1) better capture patient-derived therapeutic biomarkers compared to models trained on CCL data, (2) can be robustly validated across independent PDX cohorts, and (3) could contribute to the development of future therapeutic biomarkers.
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Affiliation(s)
- Umberto Perron
- Human Technopole, Milano, Italy
- Omniscope España, Barcelona, Spain
| | - Elena Grassi
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Aikaterini Chatzipli
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Marco Viviani
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Emre Karakoc
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Lucia Trastulla
- Human Technopole, Milano, Italy
- Open Targets, Wellcome Genome Campus, Hinxton, UK
| | - Lorenzo M Brochier
- Human Technopole, Milano, Italy
- Nerviano Medical Sciences, Milan, Nerviano, Italy
| | - Claudio Isella
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | | | - Hagen Klett
- Charles River Germany GmbH, Freiburg, Germany
| | - Ivan Molineris
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | | | - Manel Esteller
- Josep Carreras Leukemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain
| | - Enzo Medico
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Nathalie Conte
- European Molecular Biology Laboratory European Bioinformatics Institute, Cambridge, UK
| | - Ultan McDermott
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- AstraZeneca Oncology R&D, Cambridge, UK
| | - Livio Trusolino
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy.
- Department of Oncology, University of Torino, Candiolo, Torino, Italy.
| | - Andrea Bertotti
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy.
- Department of Oncology, University of Torino, Candiolo, Torino, Italy.
| | - Francesco Iorio
- Human Technopole, Milano, Italy.
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
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16
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Liang Y, Lin H, Jiang Z, Zhao Q, Cui R, Li S. HOXB8 mediates resistance to cetuximab in colorectal cancer cells through activation of the STAT3 pathway. Discov Oncol 2024; 15:603. [PMID: 39472327 PMCID: PMC11522251 DOI: 10.1007/s12672-024-01440-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/08/2024] [Indexed: 11/02/2024] Open
Abstract
Homeobox B8 (HOXB8) belongs to the HOX family and was essential to the development of colorectal carcinoma. Among the prevalent monoclonal antibodies for treating RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients, cetuximab stands out, but resistance to cetuximab frequently arises in targeted treatments. Currently, the role of HOXB8 in cetuximab-resistant mCRC remains unclear. By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
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Affiliation(s)
- Yunan Liang
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou, 325035, Zhejiang, China
| | - Han Lin
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou, 325035, Zhejiang, China
| | - Zongsheng Jiang
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou, 325035, Zhejiang, China
| | - Qi Zhao
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou, 325035, Zhejiang, China
| | - Ri Cui
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou, 325035, Zhejiang, China.
| | - Shaotang Li
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China.
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou, 325035, Zhejiang, China.
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17
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Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 2024; 9:266. [PMID: 39370455 PMCID: PMC11456611 DOI: 10.1038/s41392-024-01953-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.
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Affiliation(s)
- Qing Li
- The Shapingba Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shan Geng
- Central Laboratory, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Chongqing Municipal Health and Health Committee, Chongqing, China
| | - Ya-Qi Mo
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Lu Wang
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Guan-Bin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Jian-Peng Sheng
- College of Artificial Intelligence, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China.
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18
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Zhang R, Su C, Jia Y, Xing M, Jin S, Zong H. Molecular mechanisms of HER2-targeted therapy and strategies to overcome the drug resistance in colorectal cancer. Biomed Pharmacother 2024; 179:117363. [PMID: 39236476 DOI: 10.1016/j.biopha.2024.117363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024] Open
Abstract
HER2 amplification is one of the mechanisms that induce drug resistance to anti-EGFR therapy in colorectal cancer. In recent years, data from several randomized clinical trials show that anti-HER2 therapies improved the prognosis of patients with HER2-positive colorectal cancer. These results indicate that HER2 is a promising therapeutic target in advanced colorectal cancer. Despite the anti-HER2 therapies including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates improving the outcomes, less than 30 % of the patients achieve objective response and eventually have drug resistance. It is necessary to explore the primary and secondary mechanisms for the resistance to anti-HER2 therapies, which will pave the way to overcome the drug resistance. Several studies have reported the potential mechanisms for the resistance to anti-HER2 therapies. In this review, we present a comprehensive overview of the recent advances in clinical research, mechanisms of treatment resistance, and strategies for reversing resistance in HER2-positive colorectal cancer patients.
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Affiliation(s)
- Rui Zhang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Chang Su
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Yongliang Jia
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
| | - Menglu Xing
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Shuiling Jin
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Hong Zong
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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19
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Khattri A, Sheikh N, Agrawal N, Kaushik S, Kochanny S, Ginat D, Lingen MW, Blair E, Seiwert TY. Switching anti-EGFR antibody re-sensitizes head and neck cancer patient following acquired resistance to cetuximab. Cancer Gene Ther 2024; 31:1477-1485. [PMID: 39085630 DOI: 10.1038/s41417-024-00812-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 07/04/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024]
Abstract
Cetuximab induces responses in about 13% of head and neck squamous cell carcinomas (HNSCC). We describe the molecular mechanism of acquired resistance to cetuximab, which could be overcome by switching to a different anti-EGFR antibody. Biopsies were collected at three different time points: before the start of cetuximab (PRE-cetux), at acquired resistance to cetuximab (AR-cetux), and at acquired resistance to duligotuzumab (AR-duligo). Biopsies were analyzed using tumor and normal whole-exome sequencing, RNASeq, and targeted panel sequencing with ultra-deep coverage to generate differential mutation and expression profiles. WES and targeted sequencing analysis identified an EGFR p.G465R extracellular domain mutation in AR-cetux biopsy. Furthermore, RNASeq confirmed the expression of this mutation in the tumor tissue. This mutation prevented the binding of cetuximab to EGFR and was not present in PRE-cetux and AR-duligo biopsies, suggesting a potential mechanism of acquired resistance to cetuximab. Molecular dynamic simulations confirmed that duligotuzumab effectively binds EGFR with a p.G465R mutation. Interestingly, the p.G465R mutation improved the stability of the duligotuzumab-EGFR complex as compared to the wild-type EGFR. This is the first report of an EGFR ECD mutation associated with acquired resistance to cetuximab, posing a need for further validation. We suggest appropriate serial mutational profiling to identify ECD mutations should be considered for select patients with initial cetuximab benefit.
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Affiliation(s)
- Arun Khattri
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine, Chicago, IL, USA.
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi, India.
| | - Nizamuddin Sheikh
- Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nikhil Agrawal
- College of Health Sciences, Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Westville, Durban, South Africa
| | - Sandeep Kaushik
- Formerly at 3Bs Research Group, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Guimaraes, Portugal
| | - Sara Kochanny
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine, Chicago, IL, USA
| | - Daniel Ginat
- Department of Radiology, The University of Chicago Medicine, Chicago, IL, USA
| | - Mark W Lingen
- Department of Pathology, The University of Chicago Medicine, Chicago, IL, USA
| | - Elizabeth Blair
- Department of Surgery, The University of Chicago Medicine, Chicago, IL, USA
| | - Tanguy Y Seiwert
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine, Chicago, IL, USA.
- Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
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20
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Quaquarini E, Grillo F, Gervaso L, Arpa G, Fazio N, Vanoli A, Parente P. Prognostic and Predictive Roles of HER2 Status in Non-Breast and Non-Gastroesophageal Carcinomas. Cancers (Basel) 2024; 16:3145. [PMID: 39335117 PMCID: PMC11430748 DOI: 10.3390/cancers16183145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 09/01/2024] [Accepted: 09/07/2024] [Indexed: 09/30/2024] Open
Abstract
The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12). It encodes a tyrosine kinase receptor, the human epidermal growth factor receptor 2 (HER2), involved in neoplastic proliferation, tumor angiogenesis, and invasiveness. Over the past years, the introduction of various anti-HER2 therapies has significantly improved outcomes for patients with HER2-positive breast and gastroesophageal carcinomas. More recently, the introduction of a new antibody-drug conjugate, that is trastuzumab deruxtecan, expanded the therapeutic options to low-HER2 breast and gastroesophageal tumors. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers. We critically analyzed the key published studies, focusing on utilized scoring systems and assays used, and analyzed clinical parameters and therapeutic approaches. Although the evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal has been widely increasing over the last decade, it still remains investigational, revealing a tumor site-related prognostic and predictive value of the different types of HER2 alterations. However, standardized and validated scoring system assays have not been well-established for many organs.
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Affiliation(s)
- Erica Quaquarini
- Medical Oncology Unit of Pavia Institute, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy;
| | - Federica Grillo
- Anatomic Pathology Unit, University of Genova and Policlinico San Martino Hospital, 16132 Genova, Italy;
| | - Lorenzo Gervaso
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (L.G.); (N.F.)
| | - Giovanni Arpa
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
- Anatomic Pathology Unit of Pavia Institute, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (L.G.); (N.F.)
| | - Alessandro Vanoli
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
- Anatomic Pathology Unit, Fondazione IRCCS San Matteo Hospital, 27100 Pavia, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
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21
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Chen Y, Lu A, Hu Z, Li J, Lu J. ERBB3 targeting: A promising approach to overcoming cancer therapeutic resistance. Cancer Lett 2024; 599:217146. [PMID: 39098760 DOI: 10.1016/j.canlet.2024.217146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/21/2024] [Accepted: 07/29/2024] [Indexed: 08/06/2024]
Abstract
Human epidermal growth factor receptor-3 (ERBB3) is a member of the ERBB receptor tyrosine kinases (RTKs) and is expressed in many malignancies. Along with other ERBB receptors, ERBB3 is associated with regulating normal cell proliferation, apoptosis, differentiation, and survival, and has received increased research attention for its involvement in cancer therapies. ERBB3 expression or co-expression levels have been investigated as predictive factors for cancer prognosis and drug sensitivity. Additionally, the association between the elevated expression of ERBB3 and treatment failure in cancer therapy further established ERBB3-targeting therapy as a crucial therapeutic approach. This review delves into the molecular mechanisms of ERBB3-driven resistance to targeted therapeutics against ERBB2 and EGFR and other signal transduction inhibitors, endocrine therapy, chemotherapy, and radiotherapy. Using preclinical and clinical evidence, we synthesise and explicate how various aspects of aberrant ERBB3 activities-such as compensatory activation, signal crosstalk interactions, dysregulation in the endocytic pathway, mutations, ligand-independent activation, intrinsic kinase activity, and homodimerisation-can lead to resistance development and/or treatment failures. Several ERBB3-directed monoclonal antibodies, bispecific antibodies, and the emerging antibody-drug conjugate demonstrate encouraging clinical outcomes for improving therapeutic efficacy and overcoming resistance, especially when combined with other anti-cancer approaches. More research efforts are needed to identify appropriate biomarkers tailored for ERBB3-targeted therapies.
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Affiliation(s)
- Yutao Chen
- Auckland Bioengineering Institute, University of Auckland, Auckland, 1142, New Zealand
| | - Anni Lu
- Pinehurst School, Albany, Auckland, New Zealand
| | - Zhangli Hu
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Jinyao Li
- College of Life Sciences, Xijiang University, Urumqi, China
| | - Jun Lu
- Auckland Bioengineering Institute, University of Auckland, Auckland, 1142, New Zealand; College of Food Engineering and Nutrition Sciences, Shaanxi Normal University, Xi'an, 710119, Shaanxi Province, China; College of Food Science and Technology, Nanchang University, Nanchang, 330031, Jiangxi Province, China; Department of Food and Agriculture Technology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, Jiaxing, 314006, China.
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22
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Ou X, Gao G, Habaz IA, Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm (Beijing) 2024; 5:e694. [PMID: 39184861 PMCID: PMC11344283 DOI: 10.1002/mco2.694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 07/24/2024] [Accepted: 07/28/2024] [Indexed: 08/27/2024] Open
Abstract
Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on-target mechanisms and off-target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next-generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual-targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI-targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual-acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI-targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.
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Affiliation(s)
- Xuejin Ou
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Ge Gao
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
- Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China HospitalSichuan UniversityChengduChina
| | - Inbar A. Habaz
- Department of Biochemistry and Biomedical SciencesMcMaster UniversityHamiltonOntarioCanada
| | - Yongsheng Wang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
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23
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Huang P, Ji F, Cheung AHK, Fu K, Zhou Q, Ding X, Chen D, Lin Y, Wang L, Jiao Y, Chu ESH, Kang W, To KF, Yu J, Wong CC. Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK. Cell Host Microbe 2024; 32:1365-1379.e10. [PMID: 39059397 DOI: 10.1016/j.chom.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/23/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024]
Abstract
Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in ApcMin/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/β4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/β4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAFV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.
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Affiliation(s)
- Pingmei Huang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Fenfen Ji
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alvin Ho-Kwan Cheung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Kaili Fu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Qiming Zhou
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao Ding
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Danyu Chen
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yufeng Lin
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Luyao Wang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ying Jiao
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Eagle S H Chu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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24
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Cortese M, Torchiaro E, D'Andrea A, Petti C, Invrea F, Franco L, Donini C, Leuci V, Leto SM, Vurchio V, Cottino F, Isella C, Arena S, Vigna E, Bertotti A, Trusolino L, Sangiolo D, Medico E. Preclinical efficacy of a HER2 synNotch/CEA-CAR combinatorial immunotherapy against colorectal cancer with HER2 amplification. Mol Ther 2024; 32:2741-2761. [PMID: 38894542 PMCID: PMC11405179 DOI: 10.1016/j.ymthe.2024.06.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 05/03/2024] [Accepted: 06/14/2024] [Indexed: 06/21/2024] Open
Abstract
HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network. The natural killer (NK) cell line NK-92 was engineered with an anti-HER2 synNotch receptor driving the expression of a CAR against CEA only when engaged. After being transduced and sorted for HER2-driven CAR expression, cells were cloned. The clone with optimal performances in terms of specificity and amplitude of CAR induction demonstrated significant activity in vitro and in vivo specifically against HER2-amplified (HER2amp)/CEA+ CRC models, with no effects on cells with physiological HER2 levels. The HER2-synNotch/CEA-CAR-NK system provides an innovative, scalable, and safe off-the-shelf cell therapy approach with potential against HER2amp CRC resistant or partially responsive to HER2/EGFR blockade.
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MESH Headings
- Colorectal Neoplasms/therapy
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/immunology
- Humans
- Receptor, ErbB-2/metabolism
- Receptor, ErbB-2/genetics
- Animals
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/metabolism
- Mice
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
- Carcinoembryonic Antigen/immunology
- Carcinoembryonic Antigen/genetics
- Gene Amplification
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Immunotherapy/methods
- Immunotherapy, Adoptive/methods
- Disease Models, Animal
- Female
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Affiliation(s)
- Marco Cortese
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy.
| | - Erica Torchiaro
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Alice D'Andrea
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Consalvo Petti
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Federica Invrea
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy
| | - Letizia Franco
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy
| | - Chiara Donini
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Valeria Leuci
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | | | | | | | - Claudio Isella
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Sabrina Arena
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Elisa Vigna
- University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Andrea Bertotti
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Livio Trusolino
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Dario Sangiolo
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy
| | - Enzo Medico
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy.
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25
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Lin Z, Schaefer K, Lui I, Yao Z, Fossati A, Swaney DL, Palar A, Sali A, Wells JA. Multiscale photocatalytic proximity labeling reveals cell surface neighbors on and between cells. Science 2024; 385:eadl5763. [PMID: 39024454 DOI: 10.1126/science.adl5763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 06/10/2024] [Indexed: 07/20/2024]
Abstract
Proximity labeling proteomics (PLP) strategies are powerful approaches to yield snapshots of protein neighborhoods. Here, we describe a multiscale PLP method with adjustable resolution that uses a commercially available photocatalyst, Eosin Y, which upon visible light illumination activates different photo-probes with a range of labeling radii. We applied this platform to profile neighborhoods of the oncogenic epidermal growth factor receptor and orthogonally validated more than 20 neighbors using immunoassays and AlphaFold-Multimer prediction. We further profiled the protein neighborhoods of cell-cell synapses induced by bispecific T cell engagers and chimeric antigen receptor T cells. This integrated multiscale PLP platform maps local and distal protein networks on and between cell surfaces, which will aid in the systematic construction of the cell surface interactome, revealing horizontal signaling partners and reveal new immunotherapeutic opportunities.
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Affiliation(s)
- Zhi Lin
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Kaitlin Schaefer
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Irene Lui
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Zi Yao
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Andrea Fossati
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
- Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA
- J. David Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Danielle L Swaney
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
- Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA
- J. David Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Ajikarunia Palar
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
- Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Andrej Sali
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
- Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
| | - James A Wells
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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26
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Wahoski CC, Singh B. The Roles of RAC1 and RAC1B in Colorectal Cancer and Their Potential Contribution to Cetuximab Resistance. Cancers (Basel) 2024; 16:2472. [PMID: 39001533 PMCID: PMC11240352 DOI: 10.3390/cancers16132472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for CRC. Unfortunately, many patients develop resistance to these treatments. Cetuximab, the first targeted therapy approved to treat advanced CRC, is a monoclonal antibody that targets the epidermal growth factor receptor and inhibits downstream pathway activation to restrict tumor cell growth and proliferation. CRC resistance to cetuximab has been well studied, and common resistance mechanisms include constitutive signal transduction through downstream protein mutations and promotion of the epithelial-to-mesenchymal transition. While the most common resistance mechanisms are known, a proportion of patients develop resistance through unknown mechanisms. One protein predicted to contribute to therapy resistance is RAC1, a small GTPase that is involved in cytoskeleton rearrangement, cell migration, motility, and proliferation. RAC1 has also been shown to be overexpressed in CRC. Despite evidence that RAC1 and its alternative splice isoform RAC1B play important roles in CRC and the pathways known to contribute to cetuximab resistance, there is a need to directly study the relationship between RAC1 and RAC1B and cetuximab resistance. This review highlights the recent studies investigating RAC1 and RAC1B in the context of CRC and suggests that these proteins could play a role in resistance to cetuximab.
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Affiliation(s)
- Claudia C. Wahoski
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Bhuminder Singh
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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27
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Momeny M, Tienhaara M, Sharma M, Chakroborty D, Varjus R, Takala I, Merisaari J, Padzik A, Vogt A, Paatero I, Elenius K, Laajala TD, Kurppa KJ, Westermarck J. DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer. EMBO Mol Med 2024; 16:1603-1629. [PMID: 38886591 PMCID: PMC11251193 DOI: 10.1038/s44321-024-00088-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 05/08/2024] [Accepted: 05/24/2024] [Indexed: 06/20/2024] Open
Abstract
Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.
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Affiliation(s)
- Majid Momeny
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
| | - Mari Tienhaara
- Medicity Research Laboratories, Faculty of Medicine, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Mukund Sharma
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Deepankar Chakroborty
- Medicity Research Laboratories, Faculty of Medicine, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Roosa Varjus
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Iina Takala
- Medicity Research Laboratories, Faculty of Medicine, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Joni Merisaari
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Artur Padzik
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Andreas Vogt
- University of Pittsburgh Drug Discovery Institute, Department of Computational and Systems Biology, Pittsburgh Technology Center, Pittsburgh, PA, USA
| | - Ilkka Paatero
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Klaus Elenius
- Medicity Research Laboratories, Faculty of Medicine, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Teemu D Laajala
- Department of Mathematics and Statistics, University of Turku, Turku, Finland
| | - Kari J Kurppa
- Medicity Research Laboratories, Faculty of Medicine, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Jukka Westermarck
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
- Institute of Biomedicine, University of Turku, Turku, Finland.
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Tardito S, Matis S, Zocchi MR, Benelli R, Poggi A. Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance. Int J Mol Sci 2024; 25:7131. [PMID: 39000238 PMCID: PMC11241078 DOI: 10.3390/ijms25137131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, the need for new therapeutic strategies is still a challenge. Surgery and chemotherapy represent the first-line interventions; nevertheless, the prognosis for metastatic CRC (mCRC) patients remains unacceptable. An important step towards targeted therapy came from the inhibition of the epidermal growth factor receptor (EGFR) pathway, by the anti-EGFR antibody, Cetuximab, or by specific tyrosine kinase inhibitors (TKI). Cetuximab, a mouse-human chimeric monoclonal antibody (mAb), binds to the extracellular domain of EGFR thus impairing EGFR-mediated signaling and reducing cell proliferation. TKI can affect the EGFR biochemical pathway at different steps along the signaling cascade. Apart from Cetuximab, other anti-EGFR mAbs have been developed, such as Panitumumab. Both antibodies have been approved for the treatment of KRAS-NRAS wild type mCRC, alone or in combination with chemotherapy. These antibodies display strong differences in activating the host immune system against CRC, due to their different immunoglobulin isotypes. Although anti-EGFR antibodies are efficient, drug resistance occurs with high frequency. Resistant tumor cell populations can either already be present before therapy or develop later by biochemical adaptations or new genomic mutations in the EGFR pathway. Numerous efforts have been made to improve the efficacy of the anti-EGFR mAbs or to find new agents that are able to block downstream EGFR signaling cascade molecules. Indeed, we examined the importance of analyzing the anti-EGFR antibody-drug conjugates (ADC) developed to overcome resistance and/or stimulate the tumor host's immunity against CRC growth. Also, patient-derived CRC organoid cultures represent a useful and feasible in vitro model to study tumor behavior and therapy response. Organoids can reflect tumor genetic heterogeneity found in the tissue of origin, representing a unique tool for personalized medicine. Thus, CRC-derived organoid cultures are a smart model for studying the tumor microenvironment and for the preclinical assay of anti-EGFR drugs.
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Affiliation(s)
- Samuele Tardito
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC 20010, USA;
| | - Serena Matis
- Molecular Oncology and Angiogenesis Unit, IRRCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Maria Raffaella Zocchi
- Department of Immunology, Transplant and Infectious Diseases, IRCCS Scientific Institute San Raffaele, 20132 Milan, Italy;
| | - Roberto Benelli
- Molecular Oncology and Angiogenesis Unit, IRRCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Alessandro Poggi
- Molecular Oncology and Angiogenesis Unit, IRRCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
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Shalaby A, Mahmoud HA, Sayed SG, Al Hashmi K, Al-Sinawi S, Al Badi S, Al Rashdi A, Al Husaini S, Al Badi H, Saad El-Din SA. Evaluation of the Expression EGFR, HER2/NEU and the End Effector ERK of the RAS/RAF/MAP Kinase Pathway in Prostatic Adenocarcinoma for a Possible Role as New Target Therapy. Asian Pac J Cancer Prev 2024; 25:2193-2201. [PMID: 38918683 PMCID: PMC11382872 DOI: 10.31557/apjcp.2024.25.6.2193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Indexed: 06/27/2024] Open
Abstract
The alterations of EGFR and HER2/neu as growth factor receptors and the cytoplasmic signal transduction proteins of RAS/RAF/MAP kinases including its end effector molecule (ERK) are important in the carcinogenesis of many tumors. The activation of these protooncogenes in prostate cancer is still under investigation. The aim of this work was to study EGFR, HER2- neu, inactive (non-phosphorylated) and active (phosphorylated) ERK expression in prostatic adenocarcinomas in correlation to the clinical and pathological parameters. METHODS Immunohistochemistry- using tissue microarrays- for EGFR, HER2/neu, non-phosphorylated, and phosphor-ERK, was performed on tissues from 166 patients- with primary prostatic adenocarcinoma with no prior treatment-. The results of different markers expression were correlated with the clinical and pathological parameters and were analyzed statistically. RESULTS The prostatic tissue showed EGFR, HER2 neu, phosphorylated and non-phosphorylated ERK expression in 8.4%, 1.4%, 78.2%, and 83.4% respectively whether low (patchy) or high expression (diffuse). There were no significant correlations found between patient characteristics and expression of the tested markers. The negative immune reactivity for non-phosphorylated ERK and EGFR- was significantly correlated with high tumor stage (p values 0.03 and 0.01, respectively). CONCLUSION EGFR and HER2/neu may play a limited role in prostatic adenocarcinoma as they showed positive expression in a limited number of the examined tissues specifically HER2neu. The expression of non-phosphorylated ERK (mostly weak to moderate) and phosphorylated ERK (mostly moderate to strong)- was appreciated in most cases. Thus, we suggest that anti-EGFR drugs may have a limited role in the treatment of castrate-resistant prostate cancer, but anti-MEK/ERK drugs may have more promising role as a target therapy. It is recommended to perform further molecular testing to elucidate the exact mechanism and significance of these markers.
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Affiliation(s)
- Asem Shalaby
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Heba A Mahmoud
- Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Shayma G Sayed
- Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Khalid Al Hashmi
- Department of Hematology and Medical Oncology, Armed Forces Hospital, Muscat, Oman
| | - Shadia Al-Sinawi
- Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Suad Al Badi
- Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Afrah Al Rashdi
- Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Samya Al Husaini
- Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Hajer Al Badi
- Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Somaia Ahmed Saad El-Din
- Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
- Department of Histopathology, Armed Forces Hospital, Muscat, Oman
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Battaglin F, Ou FS, Qu X, Hochster HS, Niedzwiecki D, Goldberg RM, Mayer RJ, Ashouri K, Zemla TJ, Blanke CD, Venook AP, Kabbarah O, Lenz HJ, Innocenti F. HER2 Gene Expression Levels Are Predictive and Prognostic in Patients With Metastatic Colorectal Cancer Enrolled in CALGB/SWOG 80405. J Clin Oncol 2024; 42:1890-1902. [PMID: 38457761 PMCID: PMC11240881 DOI: 10.1200/jco.23.01507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 12/18/2023] [Accepted: 01/04/2024] [Indexed: 03/10/2024] Open
Abstract
PURPOSE The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of HER2 amplification and gene expression using next-generation sequencing (NGS) and NanoString data. PATIENTS AND METHODS Primary tumor DNA from 559 patients was profiled for HER2 amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points. RESULTS High HER2 expression (dichotomized at median) was associated with longer PFS (11.6 v 10 months, P = .012) and OS (32 v 25.3 months, P = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high HER2 expression group (P = .02), whereas a worse PFS for cetuximab was seen in the low-expression group (P = .019). When modeled as a continuous variable, increased HER2 expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted P = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted P = .0002), reaching a plateau effect after the median. In patients with HER2 expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted P = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted P = .03) compared with that with bevacizumab. A significant interaction between HER2 expression and the treatment arm was observed for OS (Pintx = .017), PFS (Pintx = .048), and objective response rate (Pintx = .001). CONCLUSION HER2 gene expression was prognostic and predictive in CALGB/SWOG 80405. HER2 tumor expression may inform treatment selection for patients with low HER2 favoring bevacizumab- versus cetuximab-based therapies.
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Affiliation(s)
- Francesca Battaglin
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
| | - Fang-Shu Ou
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | - Karam Ashouri
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
| | - Tyler J. Zemla
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
| | | | - Alan P. Venook
- University of California, San Francisco, San Francisco, CA
| | | | - Heinz-Josef Lenz
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
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31
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González NS, Marchese PV, Baraibar I, Ros J, Salvà F, Rodríguez M, Salvà C, Vaghi C, Alcaraz A, García A, Tabernero J, Élez E. Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy. Expert Opin Investig Drugs 2024; 33:613-625. [PMID: 38775361 DOI: 10.1080/13543784.2024.2349287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 04/25/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time. AREAS COVERED This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed. EXPERT OPINION Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.
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Affiliation(s)
- Nadia Saoudi González
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | | | - Iosune Baraibar
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Javier Ros
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Francesc Salvà
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Marta Rodríguez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Clara Salvà
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Caterina Vaghi
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Adriana Alcaraz
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ariadna García
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Elena Élez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
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Geng Y, Zheng X, Zhang D, Wei S, Feng J, Wang W, Zhang L, Wu C, Hu W. CircHIF1A induces cetuximab resistance in colorectal cancer by promoting HIF1α-mediated glycometabolism alteration. Biol Direct 2024; 19:36. [PMID: 38715141 PMCID: PMC11075259 DOI: 10.1186/s13062-024-00478-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 04/29/2024] [Indexed: 05/12/2024] Open
Abstract
Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.
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Affiliation(s)
- Yiting Geng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Dachuan Zhang
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Shanshan Wei
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Jun Feng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Wei Wang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Luo Zhang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
| | - Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
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Prete AA, Angerilli V, Bergamo F, Vettore V, De Toni C, Intini R, Cerma K, Ricagno G, Cerantola R, Perissinotto E, De Rosa A, Ceccon C, Gasparello J, Denaro L, D'Amico A, Chioffi F, Carcea E, Fassan M, Lonardi S. HER2 expression and genOmic characterization of rESected brain metastases from colorectal cancer: the HEROES study. Br J Cancer 2024; 130:1316-1323. [PMID: 38347094 PMCID: PMC11014920 DOI: 10.1038/s41416-023-02569-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 12/13/2023] [Accepted: 12/21/2023] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND Little is known about prognostic factors of brain metastases (BM) from colorectal cancer (CRC). HER2 amplification/overexpression (HER2+) was previously described; its impact on prognosis remains uncertain. METHODS In the translational study HEROES, extensive molecular analysis was performed on primary CRC (prCRC) and their matched resected BM by means of NGS comprehensive genomic profiling and HER2 status as assessed by immunohistochemical/ in situ hybridization. Count of tumour-infiltrating lymphocytes (TILs) was also performed. PRIMARY OBJECTIVE to describe the molecular landscape of paired BM/prCRC. SECONDARY OBJECTIVES to search for new prognostic biomarkers of outcome after BM resection: intracranial-only Progression-Free Survival (BM-iPFS), Progression-Free Survival (BM-PFS), and Overall Survival (BM-OS). RESULTS Out of 22 patients having paired samples of prCRC and BM, HER2+ was found on 4 (18%) BM, 3 (75%) of which also HER2+ in matched prCRC. Lower tumour mutation burden (HR 3.08; 95%CI 1.06-8.93; p = 0.0386) and HER2-negative BM (HER2neg) (HR 7.75;95%CI 1.97-30.40; p = 0.0033) were associated with longer BM-iPFS; HER2neg BM (HR 3.44; 95%CI 1.03-11.53; p = 0.0449) and KRASmut BM (HR 0.31; 95%CI 0.12-0.80; p = 0.0153) conferred longer BM-PFS. Longer BM-OS was found in pts with TILs-enriched (≥1.6/HPF) BM (HR 0.11; 95%CI0.01-0.91; p = 0.0403). CONCLUSIONS This study shows HER2+ enrichment in both BM and their prCRC. TILs-enriched BM conferred better BM-OS.
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Affiliation(s)
| | - Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Francesca Bergamo
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
| | - Valentina Vettore
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Chiara De Toni
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Rossana Intini
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Krisida Cerma
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | - Riccardo Cerantola
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | - Antonio De Rosa
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Carlotta Ceccon
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Jessica Gasparello
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
| | - Luca Denaro
- Academic Neurosurgery, Department of Neurosciences, University of Padua, Padua, Italy
| | - Alberto D'Amico
- Academic Neurosurgery, Department of Neurosciences, University of Padua, Padua, Italy
| | - Franco Chioffi
- Division of Neurosurgery, Azienda Ospedaliera Università di Padova, Padua, Italy
| | - Elena Carcea
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Sara Lonardi
- Medical Oncology 3, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
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Dosunmu GT, Shergill A. Colorectal Cancer: Genetic Underpinning and Molecular Therapeutics for Precision Medicine. Genes (Basel) 2024; 15:538. [PMID: 38790167 PMCID: PMC11120657 DOI: 10.3390/genes15050538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/16/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Colorectal cancer (CRC) accounts for about 10% of all cancer cases and 9% of cancer-related deaths globally. In the United States alone, CRC represents approximately 12.6% of all cancer cases, with a mortality rate of about 8%. CRC is now the first leading cause of cancer death in men younger than age 50 and second in women younger than age 50. This review delves into the genetic landscape of CRC, highlighting key mutations and their implications in disease progression and treatment. We provide an overview of the current and emerging therapeutic strategies tailored to individual genomic profiles.
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Affiliation(s)
| | - Ardaman Shergill
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA;
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35
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Ríos-Hoyo A, Monzonís X, Vidal J, Linares J, Montagut C. Unveiling acquired resistance to anti-EGFR therapies in colorectal cancer: a long and winding road. Front Pharmacol 2024; 15:1398419. [PMID: 38711991 PMCID: PMC11070789 DOI: 10.3389/fphar.2024.1398419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 04/03/2024] [Indexed: 05/08/2024] Open
Abstract
Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade, preclinical and clinical cohort studies have uncovered genomic alterations that confer a selective advantage to tumor cells under EGFR blockade, mainly downstream re-activation of RAS-MEK signaling and mutations in the extracellular domain of EGFR (EGFR-ECD). Liquid biopsies (genotyping of ctDNA) have been established as an excellent tool to easily monitor the dynamics of genomic alterations resistance in the blood of patients and to select patients for rechallenge with anti-EGFR therapies. Accordingly, several clinical trials have shown clinical benefit of rechallenge with anti-EGFR therapy in genomically-selected patients using ctDNA. However, alternative mechanisms underpinning resistance beyond genomics -mainly related to the tumor microenvironment-have been unveiled, specifically relevant in patients receiving chemotherapy-based multi-drug treatment in first line. This review explores the complexity of the multifaceted mechanisms that mediate secondary resistance to anti-EGFR therapies and potential therapeutic strategies to circumvent acquired resistance.
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Affiliation(s)
- Alejandro Ríos-Hoyo
- Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, United States
| | - Xavier Monzonís
- Department of Medical Oncology, Hospital del Mar Research Institute, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Joana Vidal
- Department of Medical Oncology, Hospital del Mar Research Institute, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Jenniffer Linares
- Department of Medical Oncology, Hospital del Mar Research Institute, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Clara Montagut
- Department of Medical Oncology, Hospital del Mar Research Institute, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
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Singh H, Sahgal P, Kapner K, Corsello SM, Gupta H, Gujrathi R, Li YY, Cherniack AD, El Alam R, Kerfoot J, Andrews E, Lee A, Nambiar C, Hannigan AM, Remland J, Brais L, Leahy ME, Rubinson DA, Schlechter BL, Meyerson M, Kuang Y, Paweletz CP, Lee JK, Quintanilha JC, Aguirre AJ, Perez KJ, Huffman BM, Rossi H, Abrams TA, Kabraji S, Trusolino L, Bertotti A, Sicinska ET, Parikh AR, Wolpin BM, Schrock AB, Giannakis M, Ng K, Meyerhardt JA, Hornick JL, Sethi NS, Cleary JM. RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer. Clin Cancer Res 2024; 30:1669-1684. [PMID: 38345769 PMCID: PMC11018475 DOI: 10.1158/1078-0432.ccr-23-2581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/17/2023] [Accepted: 02/06/2024] [Indexed: 04/16/2024]
Abstract
PURPOSE ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. EXPERIMENTAL DESIGN Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts. RESULTS ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer. CONCLUSIONS Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted.
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Affiliation(s)
- Harshabad Singh
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Pranshu Sahgal
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
- Broad Institute of Harvard and MIT, Cambridge MA, USA
| | - Kevin Kapner
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | | | - Hersh Gupta
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
- Broad Institute of Harvard and MIT, Cambridge MA, USA
| | - Rahul Gujrathi
- Department of Radiology, Boston Medical Center and Boston University, Boston, MA USA
| | - Yvonne Y. Li
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
- Broad Institute of Harvard and MIT, Cambridge MA, USA
| | - Andrew D. Cherniack
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
- Broad Institute of Harvard and MIT, Cambridge MA, USA
| | - Raquelle El Alam
- Department of Radiology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Joseph Kerfoot
- Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Elizabeth Andrews
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Annette Lee
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Chetan Nambiar
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Alison M. Hannigan
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Joshua Remland
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Lauren Brais
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Meghan E. Leahy
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Douglas A. Rubinson
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Benjamin L. Schlechter
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Matthew Meyerson
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
- Broad Institute of Harvard and MIT, Cambridge MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA USA
| | - Yanan Kuang
- Belfer Center for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA
| | - Cloud P. Paweletz
- Belfer Center for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA
| | | | | | - Andrew J. Aguirre
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
- Broad Institute of Harvard and MIT, Cambridge MA, USA
| | - Kimberly J. Perez
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Brandon M. Huffman
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Humberto Rossi
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Thomas A. Abrams
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Sheheryar Kabraji
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Livio Trusolino
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Andrea Bertotti
- Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Ewa T. Sicinska
- Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Aparna R. Parikh
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Brian M. Wolpin
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | | | - Marios Giannakis
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Kimmie Ng
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Jeffrey A. Meyerhardt
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - Jason L. Hornick
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
| | - Nilay S. Sethi
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
| | - James M. Cleary
- Dana-Farber Brigham and Women’s Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA USA
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Stahler A, Kind AJ, Sers C, Mamlouk S, Müller L, Karthaus M, Fruehauf S, Graeven U, Fischer von Weikersthal L, Sommerhäuser G, Kasper S, Hoppe B, Kurreck A, Held S, Heinemann V, Horst D, Jarosch A, Stintzing S, Trarbach T, Modest DP. Negative Hyperselection of Resistance Mutations for Panitumumab Maintenance in RAS Wild-Type Metastatic Colorectal Cancer (PanaMa Phase II Trial, AIO KRK 0212). Clin Cancer Res 2024; 30:1256-1263. [PMID: 38289994 DOI: 10.1158/1078-0432.ccr-23-3023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/21/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024]
Abstract
PURPOSE We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a 5-fluorouracil plus folinic acid (FU/FA) maintenance as pre-specified analysis of the randomized PanaMa trial. PATIENTS AND METHODS Mutations (MUT) were identified using targeted next-generation sequencing (NGS; Illumina Cancer Hotspot Panel v2) and IHC. RAS/BRAF V600E/PIK3CA/AKT1/ALK1/ERBB2/PTEN MUT and HER2/neu overexpressions were negatively hyperselected and correlated with median progression-free survival (PFS) and overall survival (OS) since start of maintenance treatment, and objective response rates (ORR). Univariate/multivariate Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI). RESULTS 202 of 248 patients (81.5%) of the full analysis set (FAS) had available NGS data: hyperselection WT, 162 (80.2%); MUT, 40 (19.8%). From start of maintenance therapy, hyperselection WT tumors were associated with longer median PFS as compared with hyperselection MUT mCRC (7.5 vs. 5.4 months; HR, 0.75; 95% CI, 0.52-1.07; P = 0.11), OS (28.7 vs. 22.2 months; HR, 0.53; 95% CI, 0.36-0.77; P = 0.001), and higher ORR (35.8% vs. 25.0%, P = 0.26). The addition of panitumumab to maintenance was associated with significant benefit in hyperselection WT tumors for PFS (9.2 vs. 6.0 months; HR, 0.66; 95% CI, 0.47-0.93; P = 0.02) and numerically also for OS (36.9 vs. 24.9 months; HR, 0.91; 95% CI, 0.61-1.36; P = 0.50), but not in hyperselection MUT tumors. Hyperselection status interacted with maintenance treatment arms in terms of PFS (P = 0.06) and OS (P = 0.009). CONCLUSIONS Extended molecular profiling beyond RAS may have the potential to improve the patient selection for anti-EGFR containing maintenance regimens.
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Affiliation(s)
- Arndt Stahler
- Department of Hematology, Oncology and Cancer Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Andreas J Kind
- Department of Hematology, Oncology and Cancer Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christine Sers
- Department of Pathology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Soulafa Mamlouk
- Department of Pathology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | | | - Meinolf Karthaus
- Department of Hematology and Oncology, Munich Hospital Neuperlach, Munich, Germany
| | | | | | | | - Greta Sommerhäuser
- Department of Hematology, Oncology and Cancer Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, Westdeutsches Tumorzentrum, University Hospital of Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site Essen, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Beeke Hoppe
- Department of Hematology, Oncology and Cancer Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Annika Kurreck
- Department of Hematology, Oncology and Cancer Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Volker Heinemann
- Department of Medicine III and Comprehensive Cancer Center, University Hospital (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site München, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - David Horst
- Department of Pathology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Armin Jarosch
- Department of Pathology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Tanja Trarbach
- Department of Medical Oncology, West German Cancer Center, Westdeutsches Tumorzentrum, University Hospital of Essen, Essen, Germany
- Reha-Zentrum am Meer, Bad Zwischenahn, Niedersachsen, Germany
| | - Dominik P Modest
- Department of Hematology, Oncology and Cancer Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Li Y, Wang B, Yang W, Ma F, Zou J, Li K, Tan S, Feng J, Wang Y, Qin Z, Chen Z, Ding C. Longitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer. Nat Commun 2024; 15:980. [PMID: 38302471 PMCID: PMC10834432 DOI: 10.1038/s41467-024-44911-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024] Open
Abstract
Cetuximab therapy is the major treatment for colorectal cancer (CRC), but drug resistance limits its effectiveness. Here, we perform longitudinal and deep proteomic profiling of 641 plasma samples originated from 147 CRC patients (CRCs) undergoing cetuximab therapy with multi-course treatment, and 90 healthy controls (HCs). COL12A1, THBS2, S100A8, and S100A9 are screened as potential proteins to distinguish CRCs from HCs both in plasma and tissue validation cohorts. We identify the potential biomarkers (RRAS2, MMP8, FBLN1, RPTOR, and IMPDH2) for the initial response prediction. In a longitudinal setting, we identify two clusters with distinct fluctuations and construct the model with high accuracy to predict the longitudinal response, further validated in the independent cohort. This study reveals the heterogeneity of different biomarkers for tumor diagnosis, the initial and longitudinal response prediction respectively in the first course and multi-course cetuximab treatment, may ultimately be useful in monitoring and intervention strategies for CRC.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bing Wang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wentao Yang
- Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fahan Ma
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianling Zou
- Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Kai Li
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Subei Tan
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinwen Feng
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunzhi Wang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaoyu Qin
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiyu Chen
- Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Chen Ding
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
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Housini M, Dariya B, Ahmed N, Stevens A, Fiadjoe H, Nagaraju GP, Basha R. Colorectal cancer: Genetic alterations, novel biomarkers, current therapeutic strategies and clinical trials. Gene 2024; 892:147857. [PMID: 37783294 DOI: 10.1016/j.gene.2023.147857] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/04/2023]
Abstract
Colorectal cancer (CRC) is the third most commonly detected cancer with a serious global health issue. The rates for incidence and mortality for CRC are alarming, especially since the prognosis is abysmal when the CRC is diagnosed at an advanced or metastatic stage. Both type of (modifiable/ non-modifiable) types of risk factors are established for CRC. Despite the advances in recent technology and sophisticated research, the survival rate is still meager due to delays in diagnosis. Therefore, there is urgently required to identify critical biomarkers aiming at early diagnosis and improving effective therapeutic strategies. Additionally, a complete understanding of the dysregulated pathways like PI3K/Akt, Notch, and Wnt associated with CRC progression and metastasis is very beneficial in designing a therapeutic regimen. This review article focused on the dysregulated signaling pathways, genetics and epigenetics alterations, and crucial biomarkers of CRC. This review also provided the list of clinical trials targeting signaling cascades and therapies involving small molecules. This review discusses up-to-date information on novel diagnostic and therapeutic strategies alongside specific clinical trials.
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Affiliation(s)
- Mohammad Housini
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - Begum Dariya
- Center for Drug Design, University of Minnesota, Minneapolis, MN 5545, United States
| | - Nadia Ahmed
- Department of Diagnostic Radiology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Alyssa Stevens
- Missouri Southern State University, Joplin, MO 64801, United States
| | - Hope Fiadjoe
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - Ganji Purnachandra Nagaraju
- Division of Hematology & Oncology, The University of Alabama at Birmingham, Birmingham, AL 35233, United States.
| | - Riyaz Basha
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, United States; Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
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Saoudi González N, Ros J, Baraibar I, Salvà F, Rodríguez-Castells M, Alcaraz A, García A, Tabernero J, Élez E. Cetuximab as a Key Partner in Personalized Targeted Therapy for Metastatic Colorectal Cancer. Cancers (Basel) 2024; 16:412. [PMID: 38254903 PMCID: PMC10814823 DOI: 10.3390/cancers16020412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/10/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
Cetuximab, a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has revolutionized personalized treatment of metastatic colorectal cancer (mCRC) patients. This review highlights the mechanism of action, characteristics, and optimal indications for cetuximab in mCRC. Cetuximab has emerged as a pivotal partner for novel therapies in specific molecular subgroups, including BRAF V600E, KRAS G12C, and HER2-altered mCRC. Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies. Ongoing clinical trials have continued to uncover innovative cetuximab-based treatment strategies, promising a brighter future for mCRC patients. This review provides a comprehensive overview of cetuximab's role and its evolving importance in personalized targeted therapy of mCRC patients, offering valuable insights into the evolving landscape of colorectal cancer treatment.
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Affiliation(s)
- Nadia Saoudi González
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Javier Ros
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Iosune Baraibar
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Francesc Salvà
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Marta Rodríguez-Castells
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Adriana Alcaraz
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Ariadna García
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
| | - Josep Tabernero
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Elena Élez
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
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Rubin E, Shan KS, Dalal S, Vu DUD, Milillo-Naraine AM, Guaqueta D, Ergle A. Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers. Int J Mol Sci 2024; 25:1064. [PMID: 38256137 PMCID: PMC10816365 DOI: 10.3390/ijms25021064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/08/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well-characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancer types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer; however, there have been strong advancements made in the incorporation of anti-HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core, incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since its groundbreaking discovery there have been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, and advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.
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Affiliation(s)
- Elizabeth Rubin
- Memorial Cancer Institute, Pembroke Pines, FL 33028, USA; (K.S.S.); (S.D.); (D.U.D.V.); (A.M.M.-N.); (D.G.); (A.E.)
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Tan YQ, Chiou YS, Guo H, Zhang S, Huang X, Dukanya D, Kumar AM, Basappa S, Liu S, Zhu T, Basappa B, Pandey V, Lobie PE. Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer. NPJ Precis Oncol 2024; 8:8. [PMID: 38200104 PMCID: PMC10781691 DOI: 10.1038/s41698-023-00489-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Aberrant activation of the PI3K/AKT signaling axis along with the sustained phosphorylation of downstream BAD is associated with a poor outcome of TNBC. Herein, the phosphorylated to non-phosphorylated ratio of BAD, an effector of PI3K/AKT promoting cell survival, was observed to be correlated with worse clinicopathologic indicators of outcome, including higher grade, higher proliferative index and lymph node metastasis. The structural optimization of a previously reported inhibitor of BAD-Ser99 phosphorylation was therefore achieved to generate a small molecule inhibiting the phosphorylation of BAD at Ser99 with enhanced potency and improved oral bioavailability. The molecule 2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(pyridin-3-yl)methyl) phenol (NCK) displayed no toxicity at supra-therapeutic doses and was therefore assessed for utility in TNBC. NCK promoted apoptosis and G0/G1 cell cycle arrest of TNBC cell lines in vitro, concordant with gene expression analyses, and reduced in vivo xenograft growth and metastatic burden, demonstrating efficacy as a single agent. Additionally, combinatorial oncology compound library screening demonstrated that NCK synergized with tyrosine kinase inhibitors (TKIs), specifically OSI-930 or Crizotinib in reducing cell viability and promoting apoptosis of TNBC cells. The synergistic effects of NCK and TKIs were also observed in vivo with complete regression of a percentage of TNBC cell line derived xenografts and prevention of metastatic spread. In patient-derived TNBC xenograft models, NCK prolonged survival times of host animals, and in combination with TKIs generated superior survival outcomes to single agent treatment. Hence, this study provides proof of concept to further develop rational and mechanistic based therapeutic strategies to ameliorate the outcome of TNBC.
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Grants
- This research was supported by the National Natural Science Foundation of China (82172618 to P.E.L. and 82102768 to Y.Q.T.), China; the Shenzhen Key Laboratory of Innovative Oncotherapeutics (ZDSYS20200820165400003 to P.E.L.) (Shenzhen Science and Technology Innovation Commission), China; Shenzhen Development and Reform Commission Subject Construction Project ([2017]1434 to P.E.L.), China; Universities Stable Funding Key Projects (WDZC20200821150704001 to P.E.L.), China; Guangdong Basic and Applied Basic Research Foundation (2020A1515111064 to Y.Q.T.), China; The Shenzhen Bay Laboratory, Oncotherapeutics (21310031 to P.E.L.), China; Overseas Research Cooperation Project (HW2020008 to V.P.) (Tsinghua Shenzhen International Graduate School), China; Research Fund, Kaohsiung Medical University (KMU-Q112002 to Y.C.), Taiwan and China Postdoctoral Science Foundation (2022M721894 to X.H.), China.
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Affiliation(s)
- Yan Qin Tan
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, People's Republic of China
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, Guangdong, People's Republic of China
| | - Yi-Shiou Chiou
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, Guangdong, People's Republic of China
- Master Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Shenzhen Bay Laboratory, Shenzhen, 518055, Guangdong, People's Republic of China
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Hui Guo
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, Guangdong, People's Republic of China
| | - Shuwei Zhang
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, Guangdong, People's Republic of China
| | - Xiaoming Huang
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, People's Republic of China
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, Guangdong, People's Republic of China
- Shenzhen Bay Laboratory, Shenzhen, 518055, Guangdong, People's Republic of China
| | - Dukanya Dukanya
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, 570006, Mysore, India
| | - Arun M Kumar
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, 570006, Mysore, India
| | - Shreeja Basappa
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, 570006, Mysore, India
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institute, Fudan University, Shanghai, People's Republic of China
| | - Tao Zhu
- Shenzhen Bay Laboratory, Shenzhen, 518055, Guangdong, People's Republic of China
- Department of Oncology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
- Hefei National Laboratory for Physical Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
| | - Basappa Basappa
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, 570006, Mysore, India.
| | - Vijay Pandey
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, People's Republic of China.
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, Guangdong, People's Republic of China.
| | - Peter E Lobie
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, People's Republic of China.
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, Guangdong, People's Republic of China.
- Shenzhen Bay Laboratory, Shenzhen, 518055, Guangdong, People's Republic of China.
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Singh H, Kang A, Bloudek L, Hsu LI, Corinna Palanca-Wessels M, Stecher M, Siadak M, Ng K. Systematic literature review and meta-analysis of HER2 amplification, overexpression, and positivity in colorectal cancer. JNCI Cancer Spectr 2024; 8:pkad082. [PMID: 37815820 PMCID: PMC10868379 DOI: 10.1093/jncics/pkad082] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/25/2023] [Accepted: 09/21/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second most common cause of cancer death globally. Recent clinical trials suggest an emerging role for HER2 as a potential clinically relevant biomarker in CRC. Testing for HER2 in CRC is not standard practice; consequently, the prevalence of HER2 positivity (HER2+) in patients with CRC remains uncertain. METHODS A systematic literature review and meta-analysis were conducted to generate estimates of proportions of patients with CRC with HER2 overexpression or HER2 amplification and HER2+ (either overexpression or amplification), overall and in patients with rat sarcoma virus (RAS) wild-type cancer. HER2+ was defined as 1) immunohistochemistry with a score of 3+, 2) immunohistochemistry with a score of 2+ and in situ hybridization+, or 3) next-generation sequencing positive. RESULTS Of 224 studies identified with information on HER2 in CRC, 52 studies used a US Food and Drug Administration-approved assay and were selected for further analysis. Estimated HER2+ rate was 4.1% (95% confidence interval [CI] = 3.4% to 5.0%) overall (n = 17 589). HER2+ rates were statistically higher in RAS wild-type (6.1%, 95% CI = 5.4% to 6.9%) vs RAS mutant CRC (1.1%, 95% CI = 0.3% to 4.4%; P < .0001). Despite limited clinical information, we confirmed enrichment of HER2+ CRC in patients with microsatellite stable and left-sided CRC. CONCLUSION This meta-analysis provides an estimate of HER2+ CRC and confirms enrichment of HER2 in microsatellite stable, left-sided, RAS wild-type CRC tumors. Our work is important given the recently described clinical efficacy of HER2-targeted therapies in HER2+ CRC and informs strategies for incorporation of HER2 testing into standard of care.
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Affiliation(s)
- Harshabad Singh
- Division of Gastrointestinal Cancers, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | | | | | | | - Kimmie Ng
- Division of Gastrointestinal Cancers, Dana-Farber Cancer Institute, Boston, MA, USA
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Hou G, Niu T, Jia A, Zhang Y, Chen X, Wei H, Jia Y, Xu Y, Li Y, Wang P, Chatterjee A. NRG1 promotes tumorigenesis and metastasis and afatinib treatment efficiency is enhanced by NRG1 inhibition in esophageal squamous cell carcinoma. Biochem Pharmacol 2023; 218:115920. [PMID: 37989416 DOI: 10.1016/j.bcp.2023.115920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/08/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with significant heterogeneity in incidence and outcomes. The role of Neuregulin 1 (NRG1) in ESCC and its contribution to aggressiveness remain unknown. This study aims to investigate the functions and molecular mechanisms of NRG1 in ESCC as well as the treatment strategy for ESCC with overexpression of NRG1. We firstly demonstrated the upregulation of NRG1 and a negative correlation trend between patients' overall survival (OS) and the expression level of NRG1 in esophageal cancer. And then we found NRG1 promoted cell proliferation, migration, inhibited apoptosis, and accelerated tumorigenesis and metastasis in ESCC using cell lines and xenograft models. Furthermore, we discovered that NRG1 activated the NF-κB/MMP9 signaling pathway, contributing to the metastatic phenotype in ESCC. Finally, we show that afatinib (FDA approved cancer growth blocker) could inhibit ESCC with overexpressed NRG1 and down-regulation of NRG1 along with afatinib treatment provides higher efficient strategy. This study uncovers the critical role and molecular mechanism of NRG1 in ESCC tumorigenesis and metastasis, suggesting its potential as a novel biomarker for ESCC treatment.
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Affiliation(s)
- Guiqin Hou
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
| | - Tengda Niu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ang Jia
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yingying Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xunan Chen
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Huiyun Wei
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yilin Jia
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yichao Xu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yan Li
- Center of Advanced Analysis & Gene Sequencing, Zhengzhou University, Zhengzhou 450001, China
| | - Pengju Wang
- Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China.
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand; School of Health Sciences and Technology, UPES, Dehradun, India.
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Yang L, Atakhanova N, Arellano MTC, Mohamed MY, Hani T, Fahdil AA, Castillo-Acobo RY, Juyal A, Hussein AK, Amin AH, Pecho RDC, Akhavan-Sigari R. Translational research of new developments in targeted therapy of colorectal cancer. Pathol Res Pract 2023; 252:154888. [PMID: 37948996 DOI: 10.1016/j.prp.2023.154888] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 10/08/2023] [Accepted: 10/11/2023] [Indexed: 11/12/2023]
Abstract
A severe global health concern is the rising incidence and mortality rate of colorectal cancer (CRC). Chemotherapy, which is typically used to treat CRC, is known to have limited specificity and can have noticeable side effects. A paradigm shift in cancer treatment has been brought about by the development of targeted therapies, which has led to the appearance of pharmacological agents with improved efficacy and decreased toxicity. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), and BRAF are among the molecular targets covered in this review that are used in targeted therapy for CRC. The current discussion also covers advancements in targeted therapeutic approaches, such as antibody-drug conjugates, immune checkpoint inhibitors, and chimeric antigen receptor (CAR) T-cell therapy. A review of the clinical trials and application of these particular therapies in treating CRC is also done. Despite the improvements in targeted therapy for CRC, problems such as drug resistance and patient selection remain to be solved. Despite this, targeted therapies have offered fresh possibilities for identifying and treating CRC, paving the way for the development of personalized medicine and extending the life expectancy and general well-being of CRC patients.
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Affiliation(s)
- Lei Yang
- Department of Clinical Laboratory, People's Hospital of Chongqing Liangjiang New Area, Chongqing 401121, China
| | - Nigora Atakhanova
- Head of the Department of Oncology, Tashkent Medical Academy, Tashkent 100109, Uzbekistan
| | | | | | - Thamer Hani
- Dentistry Department, Al-Turath University College, Baghdad, Iraq
| | - Ali A Fahdil
- Medical technical college, Al-Farahidi University, Iraq
| | | | - Ashima Juyal
- Uttaranchal Institute of Technology, Uttaranchal University, Dehradun 248007, India
| | | | - Ali H Amin
- Deanship of Scientific Research, Umm Al-Qura University, Makkah, Saudi Arabia
| | | | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Poland
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46
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Zhang Y. Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor. Pharmacol Rev 2023; 75:1218-1232. [PMID: 37339882 PMCID: PMC10595022 DOI: 10.1124/pharmrev.123.000906] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 06/22/2023] Open
Abstract
Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is activated by ligand binding, overexpression, or mutation. It is well known for its tyrosine kinase-dependent oncogenic activities in a variety of human cancers. A large number of EGFR inhibitors have been developed for cancer treatment, including monoclonal antibodies, tyrosine kinase inhibitors, and a vaccine. The EGFR inhibitors are aimed at inhibiting the activation or the activity of EGFR tyrosine kinase. However, these agents have shown efficacy in only a few types of cancers. Drug resistance, both intrinsic and acquired, is common even in cancers where the inhibitors have shown efficacy. The drug resistance mechanism is complex and not fully known. The key vulnerability of cancer cells that are resistant to EGFR inhibitors has not been identified. Nevertheless, it has been increasingly recognized in recent years that EGFR also possesses kinase-independent oncogenic functions and that these noncanonical functions may play a crucial role in cancer resistance to EGFR inhibitors. In this review, both kinase-dependent and -independent activities of EGFR are discussed. Also discussed are the mechanisms of actions and therapeutic activities of clinically used EGFR inhibitors and sustained EGFR overexpression and EGFR interaction with other receptor tyrosine kinases to counter the EGFR inhibitors. Moreover, this review discusses emerging experimental therapeutics that have shown potential for overcoming the limitation of the current EGFR inhibitors in preclinical studies. The findings underscore the importance and feasibility of targeting both kinase-dependent and -independent functions of EGFR to enhance therapeutic efficacy and minimize drug resistance. SIGNIFICANCE STATEMENT: EGFR is a major oncogenic driver and therapeutic target, but cancer resistance to current EGFR inhibitors remains a significant unmet clinical problem. This article reviews the cancer biology of EGFR as well as the mechanisms of actions and the therapeutic efficacies of current and emerging EGFR inhibitors. The findings could potentially lead to development of more effective treatments for EGFR-positive cancers.
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Affiliation(s)
- Yuesheng Zhang
- Department of Pharmacology and Toxicology, School of Medicine, and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia
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47
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Jang JY, Jeon YK, Jeong SY, Lim SH, Park YS, Lim HY, Lee JY, Kim ST. Effect of human epidermal growth factor receptor 2 overexpression in metastatic colorectal cancer on standard chemotherapy outcomes. J Gastrointest Oncol 2023; 14:2097-2110. [PMID: 37969818 PMCID: PMC10643596 DOI: 10.21037/jgo-23-375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/25/2023] [Indexed: 11/17/2023] Open
Abstract
Background In metastatic colorectal cancer (mCRC), the prognostic relevance of the human epidermal growth factor receptor-2 (HER2) remains controversial. We evaluated the impact of HER2 overexpression on outcomes of standard chemotherapy in patients with mCRC. Methods This retrospective study included patients with mCRC who received standard chemotherapy for mCRC and were tested for HER2 expression at Samsung Medical Center, Seoul, Korea, between January 15, 2017, and February 05, 2022. The HER2 test was performed using immunohistochemistry. We assessed the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) according to HER2 status. All statistical analyses were performed using SPSS® version 25 (IBM, Armonk, NY, USA). Results In total, 108 patients were included; 10 (9.3%) had HER2-positive tumors. The ORR for patients with mCRC receiving standard chemotherapy did not differ for HER2-positive and HER2-negative tumors. The median PFS for patients with mCRC with HER2-positive or HER2-tumors after receiving first-line chemotherapy was 18.52 months [95% confidence interval (CI): 4.355-32.695] or 10.95 months (95% CI: 9.317-12.585; P=0.417), respectively, and that after second-line chemotherapy was 7.08 months (95% CI: 6.801-7.363) or 5.34 months (95% CI: 4.433-6.255; P=0.837), respectively. Likewise, OS did not differ according to HER2 expression (median OS: HER2-positive tumors, 49.1 months (95% CI: 0.000-98.365); HER2-negative tumors, 37.7 months (95% CI: 27.111-48.366; P=0.410). Conclusions The tumor response and survival of patients with mCRC after standard chemotherapy did not differ by HER2 expression. These findings suggest that the status of HER2 expression need not be considered when choosing regimens as the current first- and second-line treatments.
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Affiliation(s)
- Jae Yeon Jang
- Division of Hematology-Oncology, Department of Internal Medicine, Wonju Severance Christian Hospital, Gangwon-do, Republic of Korea
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Kyung Jeon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sun Young Jeong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Hee Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jee Yun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Lin Z, Schaefer K, Lui I, Yao Z, Fossati A, Swaney DL, Palar A, Sali A, Wells JA. Multi-scale photocatalytic proximity labeling reveals cell surface neighbors on and between cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.28.564055. [PMID: 37961561 PMCID: PMC10634877 DOI: 10.1101/2023.10.28.564055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
The cell membrane proteome is the primary biohub for cell communication, yet we are only beginning to understand the dynamic protein neighborhoods that form on the cell surface and between cells. Proximity labeling proteomics (PLP) strategies using chemically reactive probes are powerful approaches to yield snapshots of protein neighborhoods but are currently limited to one single resolution based on the probe labeling radius. Here, we describe a multi-scale PLP method with tunable resolution using a commercially available histological dye, Eosin Y, which upon visible light illumination, activates three different photo-probes with labeling radii ranging from ∼100 to 3000 Å. We applied this platform to profile neighborhoods of the oncogenic epidermal growth factor receptor (EGFR) and orthogonally validated >20 neighbors using immuno-assays and AlphaFold-Multimer prediction that generated plausible binary interaction models. We further profiled the protein neighborhoods of cell-cell synapses induced by bi-specific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR)T cells at longer length scales. This integrated multi-scale PLP platform maps local and distal protein networks on cell surfaces and between cells. We believe this information will aid in the systematic construction of the cell surface interactome and reveal new opportunities for immunotherapeutics.
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49
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Majumder A. HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer. Cells 2023; 12:2517. [PMID: 37947595 PMCID: PMC10648638 DOI: 10.3390/cells12212517] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/14/2023] [Accepted: 10/20/2023] [Indexed: 11/12/2023] Open
Abstract
Human epidermal growth factor receptor 3 (HER3) is the only family member of the EGRF/HER family of receptor tyrosine kinases that lacks an active kinase domain (KD), which makes it an obligate binding partner with other receptors for its oncogenic role. When HER3 is activated in a ligand-dependent (NRG1/HRG) or independent manner, it can bind to other receptors (the most potent binding partner is HER2) to regulate many biological functions (growth, survival, nutrient sensing, metabolic regulation, etc.) through the PI3K-AKT-mTOR pathway. HER3 has been found to promote tumorigenesis, tumor growth, and drug resistance in different cancer types, especially breast and non-small cell lung cancer. Given its ubiquitous expression across different solid tumors and role in oncogenesis and drug resistance, there has been a long effort to target HER3. As HER3 cannot be targeted through its KD with small-molecule kinase inhibitors via the conventional method, pharmaceutical companies have used various other approaches, including blocking either the ligand-binding domain or extracellular domain for dimerization with other receptors. The development of treatment options with anti-HER3 monoclonal antibodies, bispecific antibodies, and different combination therapies showed limited clinical efficiency for various reasons. Recent reports showed that the extracellular domain of HER3 is not required for its binding with other receptors, which raises doubt about the efforts and applicability of the development of the HER3-antibodies for treatment. Whereas HER3-directed antibody-drug conjugates showed potentiality for treatment, these drugs are still under clinical trial. The currently understood model for dimerization-induced signaling remains incomplete due to the absence of the crystal structure of HER3 signaling complexes, and many lines of evidence suggest that HER family signaling involves more than the interaction of two members. This review article will significantly expand our knowledge of HER3 signaling and shed light on developing a new generation of drugs that have fewer side effects than the current treatment regimen for these patients.
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Affiliation(s)
- Avisek Majumder
- Department of Medicine, University of California, San Francisco, CA 94158, USA
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50
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Seo S, Keam B, Shin SH, Chae YS, Kim TM, Park LC, Hong SB, Ahn MJ, Kim SB. A phase Ia/Ib study of novel anti-ErbB3 monoclonal antibody, barecetamab (ISU104) in refractory solid cancers and monotherapy or in combination with cetuximab in recurrent or metastatic head and neck cancer. Int J Cancer 2023; 153:1501-1511. [PMID: 37357950 DOI: 10.1002/ijc.34622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/22/2023] [Accepted: 04/05/2023] [Indexed: 06/27/2023]
Abstract
We evaluated the safety, tolerability, pharmacokinetics and antitumor activity of barecetamab monotherapy and combination cetuximab therapy in patients with advanced solid cancers, especially head and neck cancer (HNC). Part 1 was a 3 + 3 dose-escalation study in which 15 patients received barecetamab at 1, 3, 5, 10 and 20 mg/kg intravenously (IV) on days 1 and 28 and weekly in patients with advanced solid cancer. Part 2 was a dose-expansion study including two patient groups with advanced HNC, including six patients receiving barecetamab at 20 mg/kg IV every 3 weeks and 12 patients receiving barecetamab and cetuximab (400 mg/m2 on day 1 followed by 250 mg/m2 every week). No dose-limiting toxicities (DLTs) were observed. Maximum serum target engagement was reached with trough levels of doses ≥3 mg/kg IV weekly. Common adverse drug reactions were diarrhea, stomatitis, dermatitis acneiform and decreased appetite. One durable complete response of more than 17 months was observed, and the overall response and disease control rates were 36.4% (4/11) and 81.1% (9/11), respectively, in the combination therapy group. In conclusion, DLT was not observed in barecetamab at 1 to 20 mg/kg. The recommended phase II dose was determined to be 20 mg/kg triweekly. Barecetamab and in cetuximab combination was well tolerated and demonstrated meaningful antitumor effects.
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Affiliation(s)
- Seyoung Seo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seong Hoon Shin
- Department of Internal Medicine, Kosin University Gospel Hospital, Busan, Republic of Korea
| | - Yee Soo Chae
- Department of Oncology/Hematology, Kyungpook National University Medical Center Biobank, Daegu, Republic of Korea
| | - Tae Min Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Lee Chun Park
- Department of Internal Medicine, Kosin University Gospel Hospital, Busan, Republic of Korea
| | - Seung-Beom Hong
- Research Center, ISU ABXIS Co., Ltd., Seongnam, Republic of Korea
| | - Myung-Ju Ahn
- Department of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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