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Kratz JD, Rehman S, Johnson KA, Gillette AA, Sunil A, Favreau PF, Pasch CA, Miller D, Zarling LC, Yeung AH, Clipson L, Anderson SJ, Steimle AK, Sprackling CM, Lemmon KK, Abbott DE, Burkard ME, Bassetti MF, Eickhoff JC, Foley EF, Heise CP, Kimple RJ, Lawson EH, LoConte NK, Lubner SJ, Mulkerin DL, Matkowskyj KA, Sanger CB, Uboha NV, Mcilwain SJ, Ong IM, Carchman EH, Skala MC, Deming DA. Subclonal response heterogeneity to define cancer organoid therapeutic sensitivity. Sci Rep 2025; 15:12072. [PMID: 40200028 PMCID: PMC11978853 DOI: 10.1038/s41598-025-96204-2] [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: 08/03/2024] [Accepted: 03/26/2025] [Indexed: 04/10/2025] Open
Abstract
Tumor heterogeneity is predicted to confer inferior clinical outcomes with precision-based strategies, however, modeling heterogeneity in a manner that still represents the tumor of origin remains a formidable challenge. Sequencing technologies are limited in their ability to identify rare subclonal populations and predict response to treatments for patients. Patient-derived organotypic cultures have significantly improved the modeling of cancer biology by faithfully representing the molecular features of primary malignant tissues. Patient-derived cancer organoid (PCO) cultures contain subclonal populations with the potential to recapitulate heterogeneity, although treatment response assessments commonly ignore diversity in the molecular profile or treatment response. Here, we demonstrate the advantage of evaluating individual PCO heterogeneity to enhance the sensitivity of these assays for predicting clinical response. Additionally, organoid subcultures identify subclonal populations with altered treatment response. Finally, dose escalation studies of PCOs to targeted anti-EGFR therapy are utilized which reveal divergent pathway expression when compared to pretreatment cultures. Overall, these studies demonstrate the importance of population-based organoid response assessments, the use of PCOs to identify molecular heterogeneity not observed with bulk tumor sequencing, and PCO heterogeneity for understanding therapeutic resistance mechanisms.
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Affiliation(s)
- Jeremy D Kratz
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Shujah Rehman
- Morgridge Institute for Research, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA
| | - Katherine A Johnson
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI, USA
| | - Amani A Gillette
- Morgridge Institute for Research, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA
| | - Aishwarya Sunil
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Peter F Favreau
- Morgridge Institute for Research, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA
| | - Cheri A Pasch
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Devon Miller
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Lucas C Zarling
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Austin H Yeung
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Linda Clipson
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI, USA
| | | | | | | | - Kayla K Lemmon
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Daniel E Abbott
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Mark E Burkard
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Michael F Bassetti
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Jens C Eickhoff
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Eugene F Foley
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Charles P Heise
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Randall J Kimple
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Elise H Lawson
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Noelle K LoConte
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Sam J Lubner
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Daniel L Mulkerin
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Kristina A Matkowskyj
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Cristina B Sanger
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Nataliya V Uboha
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Sean J Mcilwain
- Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA
| | - Irene M Ong
- Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA
| | - Evie H Carchman
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI, USA
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA
| | - Melissa C Skala
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Morgridge Institute for Research, Madison, WI, USA
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA
| | - Dustin A Deming
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA.
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI, USA.
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Dai S, Liu Y, Liu Z, Li R, Luo F, Li Y, Dai L, Peng X. Cancer-associated fibroblasts mediate resistance to anti-EGFR therapies in cancer. Pharmacol Res 2024; 206:107304. [PMID: 39002870 DOI: 10.1016/j.phrs.2024.107304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024]
Abstract
Over the last decade, epidermal growth factor receptor (EGFR)-targeted therapies have transformed the treatment landscape for patients with advanced solid tumors. Despite these advances, resistance to anti-EGFR therapies is still a significant clinical challenge. While cell-autonomous mechanisms of resistance are well-documented, they do not fully elucidate the complexity of drug resistance. Cancer-associated fibroblasts (CAFs), key mediators within the tumor microenvironment (TME), have emerged as pivotal players in cancer progression and chemoresistance. Recent evidence implicates CAFs in resistance to anti-EGFR therapies, suggesting they may undermine treatment efficacy. This review synthesizes current data, highlighting the critical role of CAFs in resistance pathogenesis and summarizing recent therapeutic strategies targeting CAFs. We underscore the challenges and advocate for the exploration of CAFs as a potential dual-targeted approach.
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Affiliation(s)
- Shuang Dai
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingtong Liu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610041, China
| | - Zheran Liu
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu Sichuan, China
| | - Ruidan Li
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu Sichuan, China
| | - Feng Luo
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yan Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Lei Dai
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu Sichuan, China.
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Mason JD, Marks E, Fan S, McCormick K, Wilson C, Harris AL, Hamdy FC, Cunningham C, Goberdhan DCI. Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer. J Extracell Vesicles 2024; 13:e12465. [PMID: 38887984 PMCID: PMC11184284 DOI: 10.1002/jev2.12465] [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: 12/21/2023] [Revised: 04/28/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.
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Affiliation(s)
- John D. Mason
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Ewan Marks
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Shih‐Jung Fan
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
- Department of Life SciencesNational Central UniversityTaoyuan CityTaiwan
| | - Kristie McCormick
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Clive Wilson
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Adrian L. Harris
- Department of Oncology, Weatherall Institute of Molecular MedicineUniversity of OxfordOxfordUK
| | - Freddie C. Hamdy
- Nuffield Department of Surgical SciencesUniversity of Oxford, John Radcliffe HospitalOxfordUK
| | - Chris Cunningham
- Nuffield Department of Surgical SciencesUniversity of Oxford, John Radcliffe HospitalOxfordUK
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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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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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Rane JK, Frankell AM, Weeden CE, Swanton C. Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies. Cancer Prev Res (Phila) 2023; 16:369-378. [PMID: 36930945 PMCID: PMC7614725 DOI: 10.1158/1940-6207.capr-22-0469] [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: 01/13/2023] [Revised: 02/17/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023]
Abstract
Histologically normal human tissues accumulate significant mutational burden with age. The extent and spectra of mutagenesis are comparable both in rapidly proliferating and post-mitotic tissues and in stem cells compared with their differentiated progeny. Some of these mutations provide increased fitness, giving rise to clones which, at times, can replace the entire surface area of tissues. Compared with cancer, somatic mutations in histologically normal tissues are primarily single-nucleotide variations. Interestingly though, the presence of these mutations and positive clonal selection in isolation remains a poor indicator of potential future cancer transformation in solid tissues. Common clonally expanded mutations in histologically normal tissues also do not always represent the most frequent early mutations in cancers of corresponding tissues, indicating differences in selection pressures. Preliminary evidence implies that stroma and immune system co-evolve with age, which may impact selection dynamics. In this review, we will explore the mutational landscape of histologically normal and premalignant human somatic tissues in detail and discuss cell-intrinsic and environmental factors that can determine the fate of positively selected mutations within them. Precisely pinpointing these determinants of cancer transformation would aid development of early cancer interventional and prevention strategies.
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Affiliation(s)
- Jayant K. Rane
- University College London Cancer Institute, London, UK
- Department of Clinical Oncology, University College London Hospitals, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Alexander M. Frankell
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Clare E. Weeden
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Department of Medical Oncology, University College London Hospitals, London, UK
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Sagawa T, Sato Y, Hirakawa M, Hamaguchi K, Tamura F, Nagashima H, Fujikawa K, Okamoto K, Kawano Y, Sogabe M, Miyamoto H, Takayama T. Case Report: Longitudinal monitoring of clonal evolution by circulating tumor DNA for resistance to anti-EGFR antibody in a case of metastatic colorectal cancer. Front Oncol 2023; 13:1203296. [PMID: 37434969 PMCID: PMC10332633 DOI: 10.3389/fonc.2023.1203296] [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: 04/10/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023] Open
Abstract
Background Treatment with anti-EGFR antibody has been shown to prolong survival in patients with RAS wild-type metastatic colorectal cancer (mCRC). However, even patients who initially respond to anti-EGFR antibody therapy, almost without exception, develop resistance to the therapy and then fail to respond. Secondary mutations in the mitogen-activated protein (MAPK) signaling pathway (mainly in NRAS and BRAF) have been implicated in anti-EGFR resistance. However, the process by which resistant clones develop during therapy has not been elucidated, and considerable intrapatient and interpatient heterogeneity exists. Circulating tumor DNA (ctDNA) testing has recently allowed the noninvasive detection of heterogeneous molecular alterations that underlie the evolution of resistance to anti-EGFR. In this report, we describe our observation of genomic alterations in KRAS and NRAS in a patient with acquired resistance to anti-EGFR antibody drugs by tracking clonal evolution using serial ctDNA anaylsis. Case presentation A 54-year-old woman was initially diagnosed with sigmoid colon cancer with multiple liver metastases. After receiving first-line mFOLFOX + cetuximab, second-line FOLFIRI + ramucirumab, third-line trifluridine/tipiracil + bevacizumab, fourth-line regorafenib, and fifth-line CAPOX + bevacizumab, she was rechallenged with CPT-11 + cetuximab. The best response to anti-EGFR rechallenge therapy was a partial response. RAS in the ctDNA was assessed during treatment. The RAS status changed from wild type to mutant type, back to wild type, and again to mutant type (NRAS/KRAS codon 61) during the course of treatment. Conclusion In this report, tracking of ctDNA allowed us to describe clonal evolution in a case in which we observed genomic alterations in KRAS and NRAS in a patient who acquired resistance to anti-EGFR antibody drugs during treatment. It is reasonable to consider repeat molecular interrogation during progression in patients with mCRC by using ctDNA analysis, which could help to identify patients who may benefit from a rechallenge strategy.
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Affiliation(s)
- Tamotsu Sagawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Hirakawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Kyoko Hamaguchi
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Fumito Tamura
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Hiroyuki Nagashima
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Koshi Fujikawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yutaka Kawano
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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Carneiro CS, Hapeman JD, Nedelcu AM. Synergistic inter-clonal cooperation involving crosstalk, co-option and co-dependency can enhance the invasiveness of genetically distant cancer clones. BMC Ecol Evol 2023; 23:20. [PMID: 37226092 DOI: 10.1186/s12862-023-02129-7] [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: 12/19/2022] [Accepted: 05/12/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Despite intensive research, cancer remains a major health problem. The difficulties in treating cancer reflect the complex nature of this disease, including high levels of heterogeneity within tumours. Intra-tumour heterogeneity creates the conditions for inter-clonal competition and selection, which could result in selective sweeps and a reduction in levels of heterogeneity. However, in addition to competing, cancer clones can also cooperate with each other, and the positive effects of these interactions on the fitness of clones could actually contribute to maintaining the heterogeneity of tumours. Consequently, understanding the evolutionary mechanisms and pathways involved in such activities is of great significance for cancer treatment. This is particularly relevant for metastasis (i.e., tumor cell migration, invasion, dispersal and dissemination), which is the most lethal phase during cancer progression. To explore if and how genetically distant clones can cooperate during migration and invasion, this study used three distinct cancer cell lines with different metastatic potentials. RESULTS We found that (i) the conditioned media from two invasive lines (breast and lung) increased the migration and invasion potential of a poorly metastatic line (breast), and (ii) this inter-clonal cooperative interaction involved the TGF-β1 signalling pathway. Furthermore, when the less aggressive line was co-cultured with the highly metastatic breast line, the invasive potential of both lines was enhanced, and this outcome was dependent on the co-option (through TGF-β1 autocrine-paracrine signalling) of the weakly metastatic clone into expressing an enhanced malignant phenotype that benefited both clones (i.e., a "help me help you" strategy). CONCLUSIONS Based on our findings, we propose a model in which crosstalk, co-option, and co-dependency can facilitate the evolution of synergistic cooperative interactions between genetically distant clones. Specifically, we suggest that synergistic cooperative interactions can easily emerge, regardless of the degree of overall genetic/genealogical relatedness, via crosstalk involving metastatic clones able to constitutively secrete molecules that induce and maintain their own malignant state (producer-responder clones) and clones that have the ability to respond to those signals (responder clones) and express a synergistic metastatic behaviour. Taking into account the lack of therapies that directly affect the metastatic process, interfering with such cooperative interactions during the early steps in the metastatic cascade could provide additional strategies to increase patient survival.
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Affiliation(s)
- Caroline S Carneiro
- Department of Biology, University of New Brunswick, Fredericton, NB, E3B 5A3, Canada
| | - Jorian D Hapeman
- Department of Biology, University of New Brunswick, Fredericton, NB, E3B 5A3, Canada
| | - Aurora M Nedelcu
- Department of Biology, University of New Brunswick, Fredericton, NB, E3B 5A3, Canada.
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Yang Y, Lu Y, Tan H, Bai M, Wang X, Ge S, Ning T, Zhang L, Duan J, Sun Y, Liu R, Li H, Ba Y, Deng T. The optimal time of starting adjuvant chemotherapy after curative surgery in patients with colorectal cancer. BMC Cancer 2023; 23:422. [PMID: 37161562 PMCID: PMC10170689 DOI: 10.1186/s12885-023-10863-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/19/2023] [Indexed: 05/11/2023] Open
Abstract
BACKGROUND Postoperative adjuvant chemotherapy (AC) is now well-accepted as standard for high-risk stage II and stage III colorectal cancer (CRC) patients, however the optimal time to initiate AC remains elusive. METHODS A comprehensive literature search was performed using the PubMed and Embase databases. The Hazard ratio (HR) with the corresponding 95% confidence interval (CI) was used as an effect measure to evaluate primary endpoints. All analyses were conducted using Stata software version 12.0 with the Random-effects model. RESULTS A total of 30 studies were included in our study. Upon comparison on overall survival (OS), we identified that delaying the initiation of AC for > 8 weeks after operation was significantly associated with poor OS (HR: 1.37; 95% CI: 1.27-1.48; P < 0.01). The poor prognostic value of AC delay for > 8 weeks was not undermined by subgroup analysis based on region, tumor site, sample size and study quality. No obvious differences were observed in survival between AC within 5-8 weeks and ≤ 4 weeks (HR: 1.03; 95% CI: 0.96 -1.10; P = 0.46). Moreover, two studies both highlighted that the survival benefit of AC was still statistically significant when AC was applied 5-6 months after surgery compared with the non-chemotherapy group. CONCLUSIONS Delaying the initiation of AC for > 8 weeks after surgery was significantly associated with poor OS. AC started within 8 weeks after surgery brought more benefits to CRC patients. There were no obvious differences in survival benefits between AC within 5-8 weeks and ≤ 4 weeks. Compared to patients not receiving AC after surgery, a delay of approximately 5-6 months was still useful to improve prognosis.
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Affiliation(s)
- Yuchong Yang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Yao Lu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Hui Tan
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ming Bai
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Xia Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Shaohua Ge
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Tao Ning
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Le Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Jingjing Duan
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Yansha Sun
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Rui Liu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Hongli Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Yi Ba
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China.
- Department of Cancer Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Ting Deng
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China.
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10
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Lee ND, Kaveh K, Bozic I. Clonal interactions in cancer: integrating quantitative models with experimental and clinical data. Semin Cancer Biol 2023; 92:61-73. [PMID: 37023969 DOI: 10.1016/j.semcancer.2023.04.002] [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: 11/30/2022] [Revised: 02/16/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023]
Abstract
Tumors consist of different genotypically distinct subpopulations-or subclones-of cells. These subclones can influence neighboring clones in a process called "clonal interaction." Conventionally, research on driver mutations in cancer has focused on their cell-autonomous effects that lead to an increase in fitness of the cells containing the driver. Recently, with the advent of improved experimental and computational technologies for investigating tumor heterogeneity and clonal dynamics, new studies have shown the importance of clonal interactions in cancer initiation, progression, and metastasis. In this review we provide an overview of clonal interactions in cancer, discussing key discoveries from a diverse range of approaches to cancer biology research. We discuss common types of clonal interactions, such as cooperation and competition, its mechanisms, and the overall effect on tumorigenesis, with important implications for tumor heterogeneity, resistance to treatment, and tumor suppression. Quantitative models-in coordination with cell culture and animal model experiments-have played a vital role in investigating the nature of clonal interactions and the complex clonal dynamics they generate. We present mathematical and computational models that can be used to represent clonal interactions and provide examples of the roles they have played in identifying and quantifying the strength of clonal interactions in experimental systems. Clonal interactions have proved difficult to observe in clinical data; however, several very recent quantitative approaches enable their detection. We conclude by discussing ways in which researchers can further integrate quantitative methods with experimental and clinical data to elucidate the critical-and often surprising-roles of clonal interactions in human cancers.
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Affiliation(s)
- Nathan D Lee
- Department of Applied Mathematics, University of Washington, Seattle, WA, United States of America
| | - Kamran Kaveh
- Department of Applied Mathematics, University of Washington, Seattle, WA, United States of America
| | - Ivana Bozic
- Department of Applied Mathematics, University of Washington, Seattle, WA, United States of America; Herbold Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.
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11
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Wu Y, Clark KC, Niranjan B, Chüeh AC, Horvath LG, Taylor RA, Daly RJ. Integrative characterisation of secreted factors involved in intercellular communication between prostate epithelial or cancer cells and fibroblasts. Mol Oncol 2023; 17:469-486. [PMID: 36608258 PMCID: PMC9980303 DOI: 10.1002/1878-0261.13376] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/05/2022] [Accepted: 01/05/2023] [Indexed: 01/07/2023] Open
Abstract
Reciprocal interactions between prostate cancer cells and carcinoma-associated fibroblasts (CAFs) mediate cancer development and progression; however, our understanding of the signalling pathways mediating these cellular interactions remains incomplete. To address this, we defined secretome changes upon co-culture of prostate epithelial or cancer cells with fibroblasts that mimic bi-directional communication in tumours. Using antibody arrays, we profiled conditioned media from mono- and co-cultures of prostate fibroblasts, epithelial and cancer cells, identifying secreted proteins that are upregulated in co-culture compared to mono-culture. Six of these (CXCL10, CXCL16, CXCL6, FST, PDGFAA, IL-17B) were functionally screened by siRNA knockdown in prostate cancer cell/fibroblast co-cultures, revealing a key role for follistatin (FST), a secreted glycoprotein that binds and bioneutralises specific members of the TGF-β superfamily, including activin A. Expression of FST by both cell types was required for the fibroblasts to enhance prostate cancer cell proliferation and migration, whereas FST knockdown in co-culture grafts decreased tumour growth in mouse xenografts. This study highlights the complexity of prostate cancer cell-fibroblast communication, demonstrates that co-culture secretomes cannot be predicted from individual cultures, and identifies FST as a tumour-microenvironment-derived secreted factor that represents a candidate therapeutic target.
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Affiliation(s)
- Yunjian Wu
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Kimberley C. Clark
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Birunthi Niranjan
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Anatomy and Developmental BiologyMonash UniversityClaytonVictoriaAustralia
| | - Anderly C. Chüeh
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
| | - Lisa G. Horvath
- Garvan Institute of Medical ResearchDarlinghurstNew South WalesAustralia
- University of SydneyNew South WalesAustralia
- Chris O'Brien LifehouseSydneyNew South WalesAustralia
| | - Renea A. Taylor
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of PhysiologyMonash UniversityClaytonVictoriaAustralia
- Cancer Research Division, Peter MacCallum Cancer CentreThe University of MelbourneVictoriaAustralia
| | - Roger J. Daly
- Cancer Program, Biomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVictoriaAustralia
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12
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Topham JT, O'Callaghan CJ, Feilotter H, Kennecke HF, Lee YS, Li W, Banks KC, Quinn K, Renouf DJ, Jonker DJ, Tu D, Chen EX, Loree JM. Circulating Tumor DNA Identifies Diverse Landscape of Acquired Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Metastatic Colorectal Cancer. J Clin Oncol 2023; 41:485-496. [PMID: 36007218 PMCID: PMC9870216 DOI: 10.1200/jco.22.00364] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
PURPOSE Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance. METHODS Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. RESULTS ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR (P = .0007), KRAS (P = .0017), LRP1B (P = .0046), ZNF217 (P = .0086), MAP2K1 (P = .018), PIK3CG (P = .018), BRAF (P = .048), and NRAS (P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR (P < .0001), SMO (P < .0001), BRAF (P < .0001), MET (P = .0002), FLT3 (P = .0002), NOTCH4 (P = .0006), ERBB2 (P = .004), and FGFR1 (P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without (P = .010). Although tumor mutation burden (TMB) did not differ pretreatment (P = .63), anti-EGFR exposure increased TMB (P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB (P = .014). CONCLUSION Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.
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Affiliation(s)
- James T. Topham
- BC Cancer, University of British Columbia, Vancouver, BC, Canada
| | | | - Harriet Feilotter
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | | | | | | | | | | | - Daniel J. Renouf
- BC Cancer, University of British Columbia, Vancouver, BC, Canada
| | - Derek J. Jonker
- The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
| | - Dongsheng Tu
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Eric X. Chen
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Jonathan M. Loree
- BC Cancer, University of British Columbia, Vancouver, BC, Canada,Jonathan M. Loree, MD, MS, University of British Columbia, BC Cancer, University of British Columbia, 600 West 10th Ave, Vancouver, BC V5Z 4E6, Canada; Twitter: @jonathanloree; e-mail:
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13
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Parseghian CM, Sun R, Woods M, Napolitano S, Lee HM, Alshenaifi J, Willis J, Nunez S, Raghav KP, Morris VK, Shen JP, Eluri M, Sorokin A, Kanikarla P, Vilar E, Rehn M, Ang A, Troiani T, Kopetz S. Resistance Mechanisms to Anti-Epidermal Growth Factor Receptor Therapy in RAS/RAF Wild-Type Colorectal Cancer Vary by Regimen and Line of Therapy. J Clin Oncol 2023; 41:460-471. [PMID: 36351210 PMCID: PMC9870238 DOI: 10.1200/jco.22.01423] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/30/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
PURPOSE Acquired resistance to anti-epidermal growth factor receptor (EGFR) inhibitor (EGFRi) therapy in colorectal cancer (CRC) has previously been explained by the model of acquiring new mutations in KRAS/NRAS/EGFR, among other MAPK-pathway members. However, this was primarily on the basis of single-agent EGFRi trials and little is known about the resistance mechanisms of EGFRi combined with effective cytotoxic chemotherapy in previously untreated patients. METHODS We analyzed paired plasma samples from patients with RAS/BRAF/EGFR wild-type metastatic CRC enrolled in three large randomized trials evaluating EGFRi in the first line in combination with chemotherapy and as a single agent in third line. The mutational signature of the alterations acquired with therapy was evaluated. CRC cell lines with resistance to cetuximab, infusional fluorouracil, leucovorin, and oxaliplatin, and SN38 were developed, and transcriptional changes profiled. RESULTS Patients whose tumors were treated with and responded to EGFRi alone were more likely to develop acquired mutations (46%) compared with those treated in combination with cytotoxic chemotherapy (9%). Furthermore, contrary to the generally accepted hypothesis of the clonal evolution of acquired resistance, we demonstrate that baseline resistant subclonal mutations rarely expanded to become clonal at progression, and most remained subclonal or disappeared. Consistent with this clinical finding, preclinical models with acquired resistance to either cetuximab or chemotherapy were cross-resistant to the alternate agents, with transcriptomic profiles consistent with epithelial-to-mesenchymal transition. By contrast, commonly acquired resistance alterations in the MAPK pathway do not affect sensitivity to cytotoxic chemotherapy. CONCLUSION These findings support a model of resistance whereby transcriptomic mechanisms of resistance predominate in the presence of active cytotoxic chemotherapy combined with EGFRi, with a greater predominance of acquired MAPK mutations after single-agent EGFRi. The proposed model has implications for prospective studies evaluating EGFRi rechallenge strategies guided by acquired MAPK mutations, and highlights the need to address transcriptional mechanisms of resistance.
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Affiliation(s)
- Christine M. Parseghian
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ryan Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Melanie Woods
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Stefania Napolitano
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Hey Min Lee
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jumanah Alshenaifi
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jason Willis
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shakayla Nunez
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kanwal P. Raghav
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Van K. Morris
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - John P. Shen
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Madhulika Eluri
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alexey Sorokin
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Preeti Kanikarla
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Eduardo Vilar
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
- Division of Cancer Prevention and Population Sciences, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | - Teresa Troiani
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Scott Kopetz
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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14
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Toulany M. Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives. Clin Transl Radiat Oncol 2022; 38:6-14. [PMID: 36313934 PMCID: PMC9596599 DOI: 10.1016/j.ctro.2022.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/06/2022] [Accepted: 10/08/2022] [Indexed: 11/06/2022] Open
Abstract
Approximately 60% of cancer patients receive curative or palliative radiation. Despite the significant role of radiotherapy (RT) as a curative approach for many solid tumors, tumor recurrence occurs, partially because of intrinsic radioresistance. Accumulating evidence indicates that the success of RT is hampered by activation of the DNA damage response (DDR). The intensity of DDR signaling is affected by multiple parameters, e.g., loss-of-function mutations in tumor suppressor genes, gain-of-function mutations in protooncogenes as well as radiation-induced alterations in signal-transduction pathways. Therefore, the response to irradiation differs in tumors of different types, which makes the individualization of RT as a rational but challenging goal. One contributor to tumor cell radiation survival is signaling through the Ras pathway. Three RAS genes encode 4 Ras isoforms: K-Ras4A, K-Ras4B, H-Ras, and N-Ras. RAS family members are found to be mutated in approximately 19% of human cancers. Mutations in RAS lead to constitutive activation of the gene product and activation of multiple Ras-dependent signal-transduction cascades. Preclinical studies have shown that the expression of mutant KRAS affects DDR and increases cell survival after irradiation. Approximately 70% of RAS mutations occur in KRAS. Thus, applying targeted therapies directly against K-Ras as well as K-Ras upstream activators and downstream effectors might be a tumor-specific approach to overcome K-Ras-mediated RT resistance. In this review, the role of K-Ras in the activation of DDR signaling will be summarized. Recent progress in targeting DDR in KRAS-mutated tumors in combination with radiochemotherapy will be discussed.
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15
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Tari H, Kessler K, Trahearn N, Werner B, Vinci M, Jones C, Sottoriva A. Quantification of spatial subclonal interactions enhancing the invasive phenotype of pediatric glioma. Cell Rep 2022; 40:111283. [PMID: 36044867 PMCID: PMC9449134 DOI: 10.1016/j.celrep.2022.111283] [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: 09/06/2021] [Revised: 03/21/2022] [Accepted: 08/08/2022] [Indexed: 11/25/2022] Open
Abstract
Diffuse midline gliomas (DMGs) are highly aggressive, incurable childhood brain tumors. They present a clinical challenge due to many factors, including heterogeneity and diffuse infiltration, complicating disease management. Recent studies have described the existence of subclonal populations that may co-operate to drive pro-tumorigenic processes such as cellular invasion. However, a precise quantification of subclonal interactions is lacking, a problem that extends to other cancers. In this study, we combine spatial computational modeling of cellular interactions during invasion with co-evolution experiments of clonally disassembled patient-derived DMG cells. We design a Bayesian inference framework to quantify spatial subclonal interactions between molecular and phenotypically distinct lineages with different patterns of invasion. We show how this approach could discriminate genuine interactions, where one clone enhanced the invasive phenotype of another, from those apparently only due to the complex dynamics of spatially restricted growth. This study provides a framework for the quantification of subclonal interactions in DMG.
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Affiliation(s)
- Haider Tari
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK; Glioma Team, The Institute of Cancer Research, London, UK
| | - Ketty Kessler
- Glioma Team, The Institute of Cancer Research, London, UK
| | - Nick Trahearn
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Benjamin Werner
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Maria Vinci
- Department of Haematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Chris Jones
- Glioma Team, The Institute of Cancer Research, London, UK.
| | - Andrea Sottoriva
- Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK; Research Centre for Computational Biology, Human Technopole, Milan, Italy.
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16
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Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer. Cancer Treat Rev 2022; 109:102433. [PMID: 35905558 DOI: 10.1016/j.ctrv.2022.102433] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 11/20/2022]
Abstract
RAS genes are the most frequently mutated oncogenes in cancer. These mutations occur in roughly half of the patients with colorectal cancer (CRC). RAS mutant tumors are resistant to therapy with anti-EGFR monoclonal antibodies. Therefore, patients with RAS mutant CRC currently have few effective therapy options. RAS mutations lead to constitutively active RAS GTPases, involved in multiple downstream signaling pathways. These alterations are associated with a tumor microenvironment (TME) that drives immune evasion and disease progression by mechanisms that remain incompletely understood. In this review, we focus on the available evidence in the literature explaining the potential effects of RAS mutations on the CRC microenvironment. Ongoing efforts to influence the TME by targeting mutant RAS and thereby sensitizing these tumors to immunotherapy will be discussed as well.
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17
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The HER family as therapeutic targets in colorectal cancer. Crit Rev Oncol Hematol 2022; 174:103681. [PMID: 35462030 DOI: 10.1016/j.critrevonc.2022.103681] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 03/30/2022] [Accepted: 04/07/2022] [Indexed: 12/23/2022] Open
Abstract
The human epidermal growth factor receptor (HER, ErbB) family has four members, epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. Although distinct in ligands and functions, all of the HER family members are receptor tyrosine kinases playing important roles in the pathogenesis of cancers. In the era of precision medicine, the HER family is one of the most important and successful cancer therapeutic targets, hallmarked by the approval of anti-EGFR therapies for the treatment of colorectal cancer and non-small cell lung cancer, and anti-HER2 therapies for the treatment of breast cancer and gastric cancer. This review briefly discusses how HER family members were discovered, their functions and roles in cancer, and most importantly, the developmental history and recent updates of therapies targeting HER family members, with colorectal cancer as a focus. We also discussed the patient selection and drug resistance to anti-EGFR therapies in the treatment of colorectal cancer.
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18
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Herpers B, Eppink B, James MI, Cortina C, Cañellas-Socias A, Boj SF, Hernando-Momblona X, Glodzik D, Roovers RC, van de Wetering M, Bartelink-Clements C, Zondag-van der Zande V, Mateos JG, Yan K, Salinaro L, Basmeleh A, Fatrai S, Maussang D, Lammerts van Bueren JJ, Chicote I, Serna G, Cabellos L, Ramírez L, Nuciforo P, Salazar R, Santos C, Villanueva A, Stephan-Otto Attolini C, Sancho E, Palmer HG, Tabernero J, Stratton MR, de Kruif J, Logtenberg T, Clevers H, Price LS, Vries RGJ, Batlle E, Throsby M. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. NATURE CANCER 2022; 3:418-436. [PMID: 35469014 DOI: 10.1038/s43018-022-00359-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 03/04/2022] [Indexed: 12/19/2022]
Abstract
Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.
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Affiliation(s)
- Bram Herpers
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | | | - Mark I James
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Carme Cortina
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Adrià Cañellas-Socias
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Sylvia F Boj
- Hubrecht Organoid Technology (HUB), Utrecht, the Netherlands
| | - Xavier Hernando-Momblona
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Dominik Glodzik
- Wellcome Sanger Institute, Hinxton, UK
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | | | - Marc van de Wetering
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | | | | | - Jara García Mateos
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | - Kuan Yan
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | | | | | | | | | | | - Irene Chicote
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Garazi Serna
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Laia Cabellos
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | - Lorena Ramírez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | - Paolo Nuciforo
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ramon Salazar
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Cristina Santos
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Alberto Villanueva
- Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain
- Xenopat SL, Parc Cientific de Barcelona (PCB), Barcelona, Spain
| | - Camille Stephan-Otto Attolini
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Elena Sancho
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
- CIBERONC, Madrid, Spain
| | - Hector G Palmer
- CIBERONC, Madrid, Spain
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | - Josep Tabernero
- CIBERONC, Madrid, Spain
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Barcelona, Spain
| | | | | | | | - Hans Clevers
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Leo S Price
- OcellO BV, Leiden, The Netherlands
- Crown Bioscience Netherlands BV, Leiden, The Netherlands
| | | | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain.
- CIBERONC, Madrid, Spain.
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
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19
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Laganà A. Computational Approaches for the Investigation of Intra-tumor Heterogeneity and Clonal Evolution from Bulk Sequencing Data in Precision Oncology Applications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1361:101-118. [DOI: 10.1007/978-3-030-91836-1_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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20
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Yu T, Gao X, Zheng Z, Zhao X, Zhang S, Li C, Liu G. Intratumor Heterogeneity as a Prognostic Factor in Solid Tumors: A Systematic Review and Meta-Analysis. Front Oncol 2021; 11:744064. [PMID: 34722299 PMCID: PMC8554141 DOI: 10.3389/fonc.2021.744064] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/17/2021] [Indexed: 11/13/2022] Open
Abstract
Background The landscape of intratumor heterogeneity (ITH) is present from the tumor evolution. ITH is a promising clinical indicator, but the association between ITH and prognosis remains controversial. Therefore, a meta-analysis was performed to explore whether ITH can serve as a valuable prognostic indicator in solid tumors. Methods All included studies were from PubMed, Embase, Cochrane, and Web of Science databases up to October 10, 2020. Studies based on ITH with available prognostic information were included. Three researchers independently completed study selection and data extraction following PRISMA guidelines. The random-effect model was used for synthesis. Hazard ratio (HR) and 95% confidence intervals (CI) were used with the endpoint defined by overall survival (OS), disease-specific survival (DFS), and progression-free survival (PFS). Results A total of 9,804 solid tumor patients from 21 studies were included. Analysis of specific cancers in the TCGA database showed similar results based on different ITH assessment methods, which provided the logical support for data consolidation. Available evidence revealed a negative relationship between ITH and prognosis for a specific cancer (such as lung cancer). However, the OS results from 14 tumor types showed that high ITH associated with shorter survival time [HR 1.65 (95% CI, 1.42-1.91)]. PFS and DFS analyses showed similar results [HR 1.89 (95% CI, 1.41-2.54) and HR 1.87 (95% CI, 1.15-3.04)] in general. The status of tumor metastasis and sampling models were not the confounding factors. Conclusions High ITH is associated with worse prognosis in many solid tumors in general although this association was absent for some cancers. ITH is expected to be a promising clinical prognostic factor for the improvement of assessment, treatment, and surveillance strategy.
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Affiliation(s)
- Tao Yu
- Department of Oncology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xin Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Institute of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Zicheng Zheng
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Institute of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xinyu Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Institute of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Shiyao Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Institute of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Chunqiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Institute of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Gang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Institute of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
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21
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Wrenn E, Huang Y, Cheung K. Collective metastasis: coordinating the multicellular voyage. Clin Exp Metastasis 2021; 38:373-399. [PMID: 34254215 PMCID: PMC8346286 DOI: 10.1007/s10585-021-10111-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/14/2021] [Indexed: 12/16/2022]
Abstract
The metastatic process is arduous. Cancer cells must escape the confines of the primary tumor, make their way into and travel through the circulation, then survive and proliferate in unfavorable microenvironments. A key question is how cancer cells overcome these multiple barriers to orchestrate distant organ colonization. Accumulating evidence in human patients and animal models supports the hypothesis that clusters of tumor cells can complete the entire metastatic journey in a process referred to as collective metastasis. Here we highlight recent studies unraveling how multicellular coordination, via both physical and biochemical coupling of cells, induces cooperative properties advantageous for the completion of metastasis. We discuss conceptual challenges and unique mechanisms arising from collective dissemination that are distinct from single cell-based metastasis. Finally, we consider how the dissection of molecular transitions regulating collective metastasis could offer potential insight into cancer therapy.
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Affiliation(s)
- Emma Wrenn
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, 98195, USA
| | - Yin Huang
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
| | - Kevin Cheung
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
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22
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Chan DKH, Buczacki SJA. Tumour heterogeneity and evolutionary dynamics in colorectal cancer. Oncogenesis 2021; 10:53. [PMID: 34272358 PMCID: PMC8285471 DOI: 10.1038/s41389-021-00342-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 06/28/2021] [Indexed: 12/25/2022] Open
Abstract
Colorectal cancer (CRC) has a global burden of disease. Our current understanding of CRC has progressed from initial discoveries which focused on the stepwise accumulation of key driver mutations, as encapsulated in the Vogelstein model, to one in which marked heterogeneity leads to a complex interplay between clonal populations. Current evidence suggests that an initial explosion, or “Big Bang”, of genetic diversity is followed by a period of neutral dynamics. A thorough understanding of this interplay between clonal populations during neutral evolution gives insights into the roles in which driver genes may participate in the progress from normal colonic epithelium to adenoma and carcinoma. Recent advances have focused not only on genetics, transcriptomics, and proteomics but have also investigated the ecological and evolutionary processes which transform normal cells into cancer. This review first describes the role which driver mutations play in the Vogelstein model and subsequently demonstrates the evidence which supports a more complex model. This article also aims to underscore the significance of tumour heterogeneity and diverse clonal populations in cancer progression.
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Affiliation(s)
- Dedrick Kok Hong Chan
- Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, UK
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23
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Crombet Ramos T, Santos Morales O, Dy GK, León Monzón K, Lage Dávila A. The Position of EGF Deprivation in the Management of Advanced Non-Small Cell Lung Cancer. Front Oncol 2021; 11:639745. [PMID: 34211836 PMCID: PMC8240591 DOI: 10.3389/fonc.2021.639745] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 05/17/2021] [Indexed: 12/22/2022] Open
Abstract
Advanced non-small cell lung cancer (NSCLC) has faced a therapeutic revolution with the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoints inhibitors (ICIs) approved for first and subsequent therapies. CIMAvax-EGF is a chemical conjugate between human-recombinant EGF and P64, a recombinant protein from Neisseria meningitides, which induces neutralizing antibodies against EGF. In the last 15 years, it has been extensively evaluated in advanced NSCLC patients. CIMAvax-EGF is safe, even after extended use, and able to keep EGF serum concentration below detectable levels. In a randomized phase III study, CIMAvax-EGF increased median overall survival of advanced NSCLC patients with at least stable disease after front-line chemotherapy. Patients bearing squamous-cell or adenocarcinomas and serum EGF concentration above 870 pg/ml had better survival compared to control patients treated with best supportive care as maintenance, confirming tumors' sensitivity to the EGF depletion. This manuscript reviews the state-of-the-art NSCLC therapy and proposes the most promising scenarios for evaluating CIMAvax-EGF, particularly in combination with TKIs or ICIs. We hypothesize that the optimal combination of CIMAvax-EGF with established therapies can further contribute to transform advanced cancer into a manageable chronic disease, compatible with years of good quality of life.
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Affiliation(s)
| | | | - Grace K. Dy
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
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24
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Russo M, Sogari A, Bardelli A. Adaptive Evolution: How Bacteria and Cancer Cells Survive Stressful Conditions and Drug Treatment. Cancer Discov 2021; 11:1886-1895. [PMID: 33952585 DOI: 10.1158/2159-8290.cd-20-1588] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cancer is characterized by loss of the regulatory mechanisms that preserve homeostasis in multicellular organisms, such as controlled proliferation, cell-cell adhesion, and tissue differentiation. The breakdown of multicellularity rules is accompanied by activation of "selfish," unicellular-like life features, which are linked to the increased adaptability to environmental changes displayed by cancer cells. Mechanisms of stress response, resembling those observed in unicellular organisms, are actively exploited by mammalian cancer cells to boost genetic diversity and increase chances of survival under unfavorable conditions, such as lack of oxygen/nutrients or exposure to drugs. Unicellular organisms under stressful conditions (e.g., antibiotic treatment) stop replicating or slowly divide and transiently increase their mutation rates to foster diversity, a process known as adaptive mutability. Analogously, tumor cells exposed to drugs enter a persister phenotype and can reduce DNA replication fidelity, which in turn fosters genetic diversity. The implications of adaptive evolution are of relevance to understand resistance to anticancer therapies.
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Affiliation(s)
- Mariangela Russo
- Department of Oncology, University of Torino, Candiolo 10060, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060, Italy.
| | - Alberto Sogari
- Department of Oncology, University of Torino, Candiolo 10060, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060, Italy
| | - Alberto Bardelli
- Department of Oncology, University of Torino, Candiolo 10060, Italy. Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060, Italy.
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25
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Dong YL, Vadla GP, Lu JYJ, Ahmad V, Klein TJ, Liu LF, Glazer PM, Xu T, Chabu CY. Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance. Commun Biol 2021; 4:374. [PMID: 33742110 PMCID: PMC7979758 DOI: 10.1038/s42003-021-01898-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 02/23/2021] [Indexed: 12/27/2022] Open
Abstract
Oncogenic RAS mutations are associated with tumor resistance to radiation therapy. Cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. However, the nature of these interactions and their role in Ras tumor radioresistance remain unclear. Here we use Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discover that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. These findings suggest that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.
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Affiliation(s)
- Yong-Li Dong
- Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA
- State Key Laboratory of Genetic Engineering and National Center for International Research, Fudan-Yale Biomedical Research Center, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China
| | - Gangadhara P Vadla
- Division of Biological Sciences, College of Veterinary Medicine, Department of Surgery, University of Missouri, Columbia, MO, USA
| | - Jin-Yu Jim Lu
- Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA
- Yale-Waterbury Internal Medicine Residency Program, Waterbury, CT, USA
| | - Vakil Ahmad
- Division of Biological Sciences, College of Veterinary Medicine, Department of Surgery, University of Missouri, Columbia, MO, USA
| | - Thomas J Klein
- Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA
- South Florida Radiation Oncology, West Palm Beach, FL, USA
| | - Lu-Fang Liu
- Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA
| | - Peter M Glazer
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
| | - Tian Xu
- Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA.
- Key Laboratory of Growth Regulation and Translation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
| | - Chiswili-Yves Chabu
- Division of Biological Sciences, College of Veterinary Medicine, Department of Surgery, University of Missouri, Columbia, MO, USA.
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26
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Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution. Cancers (Basel) 2021; 13:cancers13061380. [PMID: 33803675 PMCID: PMC8002988 DOI: 10.3390/cancers13061380] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Our manuscript summarizes the up-to-date data on the complex and dynamic nature of adaptation mechanisms and evolutionary processes taking place during cancer initiation, development and progression. Although for decades cancer has been viewed as a process governed by genetic mechanisms, it is becoming more and more clear that non-genetic mechanisms may play an equally important role in cancer evolution. In this review, we bring together these fundamental concepts and discuss how those tightly interconnected mechanisms lead to the establishment of highly adaptive quickly evolving cancers. Furthermore, we argue that in depth understanding of cancer progression from the evolutionary perspective may allow the prediction and direction of the evolutionary path of cancer populations towards drug sensitive phenotypes and thus facilitate the development of more effective anti-cancer approaches. Abstract Cancer development can be defined as a process of cellular and tissular microevolution ultimately leading to malignancy. Strikingly, though this concept has prevailed in the field for more than a century, the precise mechanisms underlying evolutionary processes occurring within tumours remain largely uncharacterized and rather cryptic. Nevertheless, although our current knowledge is fragmentary, data collected to date suggest that most tumours display features compatible with a diverse array of evolutionary paths, suggesting that most of the existing macro-evolutionary models find their avatar in cancer biology. Herein, we discuss an up-to-date view of the fundamental genetic and non-genetic mechanisms underlying tumour evolution with the aim of concurring into an integrated view of the evolutionary forces at play throughout the emergence and progression of the disease and into the acquisition of resistance to diverse therapeutic paradigms. Our ultimate goal is to delve into the intricacies of genetic and non-genetic networks underlying tumour evolution to build a framework where both core concepts are considered non-negligible and equally fundamental.
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27
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Chen C, Di Bartolomeo M, Corallo S, Strickler JH, Goyal L. Overcoming Resistance to Targeted Therapies in Gastrointestinal Cancers: Progress to Date and Progress to Come. Am Soc Clin Oncol Educ Book 2021; 40:161-173. [PMID: 32421451 DOI: 10.1200/edbk_280871] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Targeted therapies have transformed the treatment paradigm in diseases such as non-small cell lung cancer and melanoma but have shown relatively modest clinical benefit in gastrointestinal malignancies. Anti-EGFR therapy in RAS wild-type colorectal cancer, anti-HER2 therapy in HER2- amplified esophagogastric cancer, and FGFR and isocitrate dehydrogenase 1 (IDH1) inhibitors in FGFR2 fusion-positive and IDH1-mutant biliary tract cancers offer antitumor efficacy, but the clinical benefit and durability of response in each case are typically limited. We review targeted therapies in each of these therapeutic areas and discuss their clinical efficacy, mechanisms of primary and acquired resistance, and strategies to overcome this resistance. We discuss lessons learned that we hope will lead to an expanded role for molecularly targeted therapy options for patients with gastrointestinal cancers.
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Affiliation(s)
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Boston, MA
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28
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Knebel FH, Barber LJ, Newey A, Kleftogiannis D, Woolston A, Griffiths B, Fenwick K, Bettoni F, Ribeiro MFSA, da Fonseca L, Costa F, Capareli FC, Hoff PM, Sabbaga J, Camargo AA, Gerlinger M. Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy. Cancers (Basel) 2020; 12:E3736. [PMID: 33322618 PMCID: PMC7764102 DOI: 10.3390/cancers12123736] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/07/2020] [Indexed: 02/05/2023] Open
Abstract
Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.
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Affiliation(s)
- Franciele H. Knebel
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; (F.H.K.); (L.J.B.); (A.N.); (A.W.); (B.G.)
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Louise J. Barber
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; (F.H.K.); (L.J.B.); (A.N.); (A.W.); (B.G.)
| | - Alice Newey
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; (F.H.K.); (L.J.B.); (A.N.); (A.W.); (B.G.)
| | - Dimitrios Kleftogiannis
- Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK;
| | - Andrew Woolston
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; (F.H.K.); (L.J.B.); (A.N.); (A.W.); (B.G.)
| | - Beatrice Griffiths
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; (F.H.K.); (L.J.B.); (A.N.); (A.W.); (B.G.)
| | - Kerry Fenwick
- Tumour Profiling Unit, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK;
| | - Fabiana Bettoni
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Maurício Fernando Silva Almeida Ribeiro
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Leonardo da Fonseca
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Frederico Costa
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Fernanda Cunha Capareli
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Paulo M. Hoff
- Instituto D’Or de Pesquisa e Ensino, IDOR, Oncologia D’Or, Avenida República do Líbano 611, São Paulo 04.502-001, SP, Brazil;
| | - Jorge Sabbaga
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Anamaria A. Camargo
- Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, Rua Dona Adma Jafet 91, São Paulo 01308-050, SP, Brazil; (F.B.); (M.F.S.A.R.); (L.d.F.); (F.C.); (F.C.C.); (J.S.); (A.A.C.)
| | - Marco Gerlinger
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; (F.H.K.); (L.J.B.); (A.N.); (A.W.); (B.G.)
- GI Cancer Unit, The Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, UK
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Zheng Z, Yu T, Zhao X, Gao X, Zhao Y, Liu G. Intratumor heterogeneity: A new perspective on colorectal cancer research. Cancer Med 2020; 9:7637-7645. [PMID: 32853464 PMCID: PMC7571807 DOI: 10.1002/cam4.3323] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/17/2020] [Accepted: 06/29/2020] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancers generally consist of multiple subclones. These subclones have their own unique characteristics, resulting in intratumor heterogeneity (ITH). As the discussion of ITH has advanced, a model describing the relationship of ITH to the tumor has gradually emerged. ITH can be divided into two types of intraprimary tumor heterogeneity and intraindividual tumor heterogeneity, the former for further understanding of tumor composition, and the latter for providing more information about evolutionary patterns. With the rapid development of new methods, such as next‐generation, polyguanine region sequencing, and Image detection, researchers may unravel the secrets underlying ITH. The higher the ITH of the tumor, the richer the interaction between the subclones maybe, or the greater the chance of the tumor getting more powerful subclones may be, thus increasing the malignant potential of the tumor. Existing evidence suggests that ITH may increase the ability of tumors to resist treatment and can be used as an independent influence on the prognosis of colorectal cancer. We reviewed 80 recent studies to give researchers a new perspective on colorectal cancer. There is still a limited amount of research in this area. Further study of the relationship between ITH and clinical endpoints may lead to the development of new treatment strategies.
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Affiliation(s)
- Zicheng Zheng
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Tao Yu
- Department of Oncology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xinyu Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Xin Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yao Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Gang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin, China
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30
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Martini G, Ciardiello D, Vitiello PP, Napolitano S, Cardone C, Cuomo A, Troiani T, Ciardiello F, Martinelli E. Resistance to anti-epidermal growth factor receptor in metastatic colorectal cancer: What does still need to be addressed? Cancer Treat Rev 2020; 86:102023. [PMID: 32474402 DOI: 10.1016/j.ctrv.2020.102023] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/21/2022]
Abstract
Colorectal cancer (CRC) represents a global health problem, being one of the most diagnosed and aggressive tumors. Cetuximab and panitumumab monoclonal antibodies (mAbs) in combination with chemotherapy are an effective strategy for patients with RAS Wild Type (WT) metastatic colorectal cancer (mCRC). However, tumors are often unresponsive or develop resistance. In the last years, molecular alterations in principal oncogenes (RAS, BRAF, PI3KCA, PTEN) in the downstream pathway of the epidermal growth factor receptor (EGFR) and in other receptors (HER2, MET) that converge on MAPK-ERK signalling have been identified as novel mechanisms of resistance to anti-EGFR strategies. However, further efforts are needed to better stratify CRCs and ensure more individualized treatments. Herein, we describe the consolidated molecular drivers of resistance and the therapeutic strategies available so far, with an overview on potential biomarkers of response that could be integrated in clinical practice.
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Affiliation(s)
- Giulia Martini
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Davide Ciardiello
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Pietro Paolo Vitiello
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Stefania Napolitano
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Claudia Cardone
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Antonio Cuomo
- Gastroenterology Unit, Ospedale Umberto I, Nocera Inferiore, Italy
| | - Teresa Troiani
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Fortunato Ciardiello
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Erika Martinelli
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
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31
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Parseghian CM, Napolitano S, Loree JM, Kopetz S. Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies. Clin Cancer Res 2019; 25:6899-6908. [PMID: 31263029 PMCID: PMC6891150 DOI: 10.1158/1078-0432.ccr-19-0823] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/16/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023]
Abstract
Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
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Affiliation(s)
- Christine M Parseghian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Stefania Napolitano
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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32
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Lee HW, Son E, Lee K, Lee Y, Kim Y, Lee JC, Lim Y, Hur M, Kim D, Nam DH. Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts. Int J Mol Sci 2019; 20:ijms20235894. [PMID: 31771279 PMCID: PMC6928876 DOI: 10.3390/ijms20235894] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023] Open
Abstract
Epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, including cetuximab and panitumumab, are used to treat metastatic colorectal cancer (mCRC). However, this treatment is only effective for a small subset of mCRC patients positive for the wild-type KRAS GTPase. GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-affinity EGFR ligand-induced signaling and enhanced antibody-mediated cytotoxicity. In this study, using 51 CRC patient-derived xenografts (PDXs), we showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. In three KRAS-mutant CRCPDXs, GC1118 was more effective than cetuximab, whereas the two agents demonstrated comparable efficacy against three wild-type KRAS PDXs. Persistent phosphatidylinositol-3-kinase (PI3K)/AKT signaling was thought to underlie resistance to GC1118. In support of these findings, a preliminary improved anti-cancer response was observed in a CRC PDX harboring mutated KRAS with intrinsically high AKT activity using GC1118 combined with the dual PI3K/mammalian target of rapamycin (mTOR)/AKT inhibitor BEZ-235, without observed toxicity. Taken together, the superior antitumor efficacy of GC1118 alone or in combination with PI3K/mTOR/AKT inhibitors shows great therapeutic potential for the treatment of KRAS-mutant mCRC with elevated ratios of high- to low-affinity EGFR ligands and PI3K-AKT pathway activation.
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Affiliation(s)
- Hye Won Lee
- Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16149, Korea;
- Single Cell Network Research Center, Sungkyunkwan University, Suwon 16149, Korea
| | - Eunju Son
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; (E.S.); (K.L.); (Y.L.); (Y.K.)
| | - Kyoungmin Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; (E.S.); (K.L.); (Y.L.); (Y.K.)
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06351, Korea
| | - Yeri Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; (E.S.); (K.L.); (Y.L.); (Y.K.)
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
| | - Yejin Kim
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; (E.S.); (K.L.); (Y.L.); (Y.K.)
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06351, Korea
| | - Jae-Chul Lee
- Translational Research 1 Team, MOGAM Institute for Biomedical Research, Yongin 16924, Korea; (J.-C.L.); (Y.L.); (M.H.)
| | - Yangmi Lim
- Translational Research 1 Team, MOGAM Institute for Biomedical Research, Yongin 16924, Korea; (J.-C.L.); (Y.L.); (M.H.)
| | - Minkyu Hur
- Translational Research 1 Team, MOGAM Institute for Biomedical Research, Yongin 16924, Korea; (J.-C.L.); (Y.L.); (M.H.)
| | - Donggeon Kim
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; (E.S.); (K.L.); (Y.L.); (Y.K.)
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
- Correspondence: (D.K.); (D.-H.N.); Tel.: +82-02-2148-7723 (D.K.); +82-02-3410-3497 (D.-H.N.)
| | - Do-Hyun Nam
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; (E.S.); (K.L.); (Y.L.); (Y.K.)
- Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06351, Korea
- Department of Neurosurgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul 06531, Korea
- Correspondence: (D.K.); (D.-H.N.); Tel.: +82-02-2148-7723 (D.K.); +82-02-3410-3497 (D.-H.N.)
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33
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Davis JB, Krishna SS, Abi Jomaa R, Duong CT, Espina V, Liotta LA, Mueller C. A new model isolates glioblastoma clonal interactions and reveals unexpected modes for regulating motility, proliferation, and drug resistance. Sci Rep 2019; 9:17380. [PMID: 31758030 PMCID: PMC6874607 DOI: 10.1038/s41598-019-53850-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
Tumor clonal heterogeneity drives treatment resistance. But robust models are lacking that permit eavesdropping on the basic interaction network of tumor clones. We developed an in vitro, functional model of clonal cooperation using U87MG glioblastoma cells, which isolates fundamental clonal interactions. In this model pre-labeled clones are co-cultured to track changes in their individual motility, growth, and drug resistance behavior while mixed. This highly reproducible system allowed us to address a new class of fundamental questions about clonal interactions. We demonstrate that (i) a single clone can switch off the motility of the entire multiclonal U87MG cell line in 3D culture, (ii) maintenance of clonal heterogeneity is an intrinsic and influential cancer cell property, where clones coordinate growth rates to protect slow growing clones, and (iii) two drug sensitive clones can develop resistance de novo when cooperating. Furthermore, clonal communication for these specific types of interaction did not require diffusible factors, but appears to depend on cell-cell contact. This model constitutes a straightforward but highly reliable tool for isolating the complex clonal interactions that make up the fundamental "hive mind" of the tumor. It uniquely exposes clonal interactions for future pharmacological and biochemical studies.
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Affiliation(s)
- Justin B Davis
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA
| | - Sreshta S Krishna
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA
| | - Ryan Abi Jomaa
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA
| | - Cindy T Duong
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA
| | - Virginia Espina
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA
| | - Lance A Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA
| | - Claudius Mueller
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA, 20110, USA.
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34
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Parakh S, King D, Gan HK, Scott AM. Current Development of Monoclonal Antibodies in Cancer Therapy. Recent Results Cancer Res 2019; 214:1-70. [PMID: 31473848 DOI: 10.1007/978-3-030-23765-3_1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.
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Affiliation(s)
- Sagun Parakh
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Melbourne, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Dylan King
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Hui K Gan
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Melbourne, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Andrew M Scott
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia. .,School of Cancer Medicine, La Trobe University, Melbourne, Australia. .,Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia. .,Department of Medicine, University of Melbourne, Melbourne, Australia.
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35
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Woolston A, Khan K, Spain G, Barber LJ, Griffiths B, Gonzalez-Exposito R, Hornsteiner L, Punta M, Patil Y, Newey A, Mansukhani S, Davies MN, Furness A, Sclafani F, Peckitt C, Jiménez M, Kouvelakis K, Ranftl R, Begum R, Rana I, Thomas J, Bryant A, Quezada S, Wotherspoon A, Khan N, Fotiadis N, Marafioti T, Powles T, Lise S, Calvo F, Guettler S, von Loga K, Rao S, Watkins D, Starling N, Chau I, Sadanandam A, Cunningham D, Gerlinger M. Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer. Cancer Cell 2019; 36:35-50.e9. [PMID: 31287991 PMCID: PMC6617392 DOI: 10.1016/j.ccell.2019.05.013] [Citation(s) in RCA: 199] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 04/01/2019] [Accepted: 05/23/2019] [Indexed: 01/05/2023]
Abstract
Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.
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Affiliation(s)
- Andrew Woolston
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Khurum Khan
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Georgia Spain
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Louise J Barber
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Beatrice Griffiths
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Reyes Gonzalez-Exposito
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Lisa Hornsteiner
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Marco Punta
- Centre for Evolution and Cancer Bioinformatics Team, The Institute of Cancer Research, London SW3 6JB, UK
| | - Yatish Patil
- Centre for Evolution and Cancer Bioinformatics Team, The Institute of Cancer Research, London SW3 6JB, UK
| | - Alice Newey
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Sonia Mansukhani
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Matthew N Davies
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Andrew Furness
- Cancer Institute, University College London, London WC1E 6AG, UK
| | | | - Clare Peckitt
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Mirta Jiménez
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | | | - Romana Ranftl
- Tumour Microenvironment Lab, The Institute of Cancer Research, London SW3 6JB, UK
| | - Ruwaida Begum
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Isma Rana
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Janet Thomas
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Annette Bryant
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Sergio Quezada
- Cancer Institute, University College London, London WC1E 6AG, UK
| | | | - Nasir Khan
- Department of Radiology, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Nikolaos Fotiadis
- Department of Radiology, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Teresa Marafioti
- Departments of Pathology and Histopathology, University College Hospital, London NW1 2PG, UK
| | - Thomas Powles
- Barts Cancer Institute, Queen Mary University, London EC1M 6BQ, UK
| | - Stefano Lise
- Centre for Evolution and Cancer Bioinformatics Team, The Institute of Cancer Research, London SW3 6JB, UK
| | - Fernando Calvo
- Tumour Microenvironment Lab, The Institute of Cancer Research, London SW3 6JB, UK
| | - Sebastian Guettler
- Division of Structural Biology, The Institute of Cancer Research, London SW3 6JB, UK
| | - Katharina von Loga
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
| | - Sheela Rao
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - David Watkins
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | | | - Ian Chau
- GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK
| | - Anguraj Sadanandam
- Systems and Precision Cancer Medicine Lab, The Institute of Cancer Research, London SW3 6JB, UK
| | | | - Marco Gerlinger
- Translational Oncogenomics Lab, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; GI Cancer Unit, The Royal Marsden Hospital, London SW3 6JJ, UK.
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36
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Glucocorticoid Receptor Modulates EGFR Feedback upon Acquisition of Resistance to Monoclonal Antibodies. J Clin Med 2019; 8:jcm8050600. [PMID: 31052457 PMCID: PMC6572202 DOI: 10.3390/jcm8050600] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 04/26/2019] [Accepted: 04/28/2019] [Indexed: 12/20/2022] Open
Abstract
Evidences of a crosstalk between Epidermal Growth Factor Receptor (EGFR) and Glucocorticoid Receptor (GR) has been reported, ranging from the modulation of receptor levels or GR mediated transcriptional repression of EGFR target genes, with modifications of epigenetic markers. The present study focuses on the involvement of EGFR positive and negative feedback genes in the establishment of cetuximab (CTX) resistance in metastatic Colorectal Cancer (CRC) patients. We evaluated the expression profile of the EGFR ligands TGFA and HBEGF, along with the pro-inflammatory cytokines IL-1B and IL-8, which were previously reported to be negatively associated with monoclonal antibody response, both in mice and patient specimens. Among EGFR negative feedback loops, we focused on ERRFI1, DUSP1, LRIG3, and LRIG1. We observed that EGFR positive feedback genes are increased in CTX-resistant cells, whereas negative feedback genes are reduced. Next, we tested the expression of these genes in CTX-resistant cells upon GR modulation. We unveiled that GR activation leads to an increase in ERRFI1, DUSP1, and LRIG1, which were shown to restrict EGFR activity, along with a decrease in the EGFR activators (TGFA and IL-8). Finally, in a cohort of xenopatients, stratified for response to cetuximab, we observed an inverse association between the expression level of LRIG1 and CRC progression upon CTX treatment. Our model implies that combining GR modulation to EGFR inhibition may yield an effective treatment strategy in halting cancer progression.
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37
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Park SH, Jo MJ, Kim BR, Jeong YA, Na YJ, Kim JL, Jeong S, Yun HK, Kim DY, Kim BG, Kang SH, Oh SC, Lee DH. Sonic hedgehog pathway activation is associated with cetuximab resistance and EPHB3 receptor induction in colorectal cancer. Am J Cancer Res 2019; 9:2235-2251. [PMID: 31149041 PMCID: PMC6531304 DOI: 10.7150/thno.30678] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 02/17/2019] [Indexed: 02/06/2023] Open
Abstract
A major problem of colorectal cancer (CRC) targeted therapies is relapse caused by drug resistance. In most cases of CRC, patients develop resistance to anticancer drugs. Cetuximab does not show many of the side effects of other anticancer drugs and improves the survival of patients with metastatic CRC. However, the molecular mechanism of cetuximab resistance is not fully understood. Methods: EPHB3-mediated cetuximab resistance was confirmed by in vitro western blotting, colony-forming assays, WST-1 colorimetric assay, and in vivo xenograft models (n = 7 per group). RNA-seq analysis and receptor tyrosine kinase assays were performed to identify the cetuximab resistance mechanism of EPHB3. All statistical tests were two-sided. Results: The expression of EFNB3, which upregulates the EPHB3 receptor, was shown to be increased via microarray analysis. When resistance to cetuximab was acquired, EPHB3 protein levels increased. Hedgehog signaling, cancer stemness, and epithelial-mesenchymal transition signaling proteins were also increased in the cetuximab-resistant human colon cancer cell line SW48R. Despite cells acquiring resistance to cetuximab, STAT3 was still responsive to EGF and cetuximab treatment. Moreover, inhibition of EPHB3 was associated with decreased STAT3 activity. Co-immunoprecipitation confirmed that EGFR and EPHB3 bind to each other and this binding increases upon resistance acquisition, suggesting that STAT3 is activated by the binding between EGFR and EPHB3. Protein levels of GLI-1, SOX2, and Vimentin, which are affected by STAT3, also increased. Similar results were obtained in samples from patients with CRC. Conclusion: EPHB3 expression is associated with anticancer drug resistance.
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38
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Dzobo K, Senthebane DA, Thomford NE, Rowe A, Dandara C, Parker MI. Not Everyone Fits the Mold: Intratumor and Intertumor Heterogeneity and Innovative Cancer Drug Design and Development. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 22:17-34. [PMID: 29356626 DOI: 10.1089/omi.2017.0174] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Disruptive innovations in medicine are game-changing in nature and bring about radical shifts in the way we understand human diseases, their treatment, and/or prevention. Yet, disruptive innovations in cancer drug design and development are still limited. Therapies that cure all cancer patients are in short supply or do not exist at all. Chief among the causes of this predicament is drug resistance, a mechanism that is much more dynamic than previously understood. Drug resistance has limited the initial success experienced with biomarker-guided targeted therapies as well. A major contributor to drug resistance is intratumor heterogeneity. For example, within solid tumors, there are distinct subclones of cancer cells, presenting profound complexity to cancer treatment. Well-known contributors to intratumor heterogeneity are genomic instability, the microenvironment, cellular genotype, cell plasticity, and stochastic processes. This expert review explains that for oncology drug design and development to be more innovative, we need to take into account intratumor heterogeneity. Initially thought to be the preserve of cancer cells, recent evidence points to the highly heterogeneous nature and diverse locations of stromal cells, such as cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (CAMs). Distinct subpopulations of CAFs and CAMs are now known to be located immediately adjacent and distant from cancer cells, with different subpopulations exerting different effects on cancer cells. Disruptive innovation and precision medicine in clinical oncology do not have to be a distant reality, but can potentially be achieved by targeting these spatially separated and exclusive cancer cell subclones and CAF subtypes. Finally, we emphasize that disruptive innovations in drug discovery and development will likely come from drugs whose effect is not necessarily tumor shrinkage.
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Affiliation(s)
- Kevin Dzobo
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa .,2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Dimakatso Alice Senthebane
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa .,2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Nicholas Ekow Thomford
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Arielle Rowe
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa
| | - Collet Dandara
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - M Iqbal Parker
- 2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
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AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer. Proc Natl Acad Sci U S A 2019; 116:3604-3613. [PMID: 30733286 DOI: 10.1073/pnas.1815126116] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.
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Bahcall M, Awad MM, Sholl LM, Wilson FH, Xu M, Wang S, Palakurthi S, Choi J, Ivanova EV, Leonardi GC, Ulrich BC, Paweletz CP, Kirschmeier PT, Watanabe M, Baba H, Nishino M, Nagy RJ, Lanman RB, Capelletti M, Chambers ES, Redig AJ, VanderLaan PA, Costa DB, Imamura Y, Jänne PA. Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non-Small Cell Lung Cancer. Clin Cancer Res 2018; 24:5963-5976. [PMID: 30072474 PMCID: PMC6279568 DOI: 10.1158/1078-0432.ccr-18-0876] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/19/2018] [Accepted: 07/23/2018] [Indexed: 01/06/2023]
Abstract
PURPOSE MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild-type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14-mutant NSCLC and propose a combination therapy to target it. EXPERIMENTAL DESIGN The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14-mutant patient tumor with massive focal amplification of WT KRAS. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy in vivo and in vitro using viability and apoptotic assays. RESULTS KRAS amplification is a recurrent genetic event in crizotinib-resistant METex14-mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition. CONCLUSIONS Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by KRAS amplification in METex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
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Affiliation(s)
- Magda Bahcall
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Lynette M Sholl
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Frederick H Wilson
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Man Xu
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Stephen Wang
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sangeetha Palakurthi
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jihyun Choi
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Elena V Ivanova
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Giulia C Leonardi
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Bryan C Ulrich
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Cloud P Paweletz
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Paul T Kirschmeier
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Mizuki Nishino
- Department of Radiology, Brigham And Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | | | | | - Marzia Capelletti
- Center for Hematologic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Emily S Chambers
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Amanda J Redig
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Paul A VanderLaan
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Daniel B Costa
- Thoracic Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
- Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Yu Imamura
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Pasi A Jänne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Barault L, Amatu A, Siravegna G, Ponzetti A, Moran S, Cassingena A, Mussolin B, Falcomatà C, Binder A, Cristiano C, Oddo D, Cancelliere C, Bustreo S, Bencardino K, Maden S, Vanzati A, Zavattari P, Truini M, Grady WM, Racca P, Michels KB, Siena S, Esteller M, Bardelli A, Sartore-Bianchi A, Di Nicolantonio F, Sartore-Bianchi A, Di Nicolantonio F. Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer. Gut 2018; 67:1995-2005. [PMID: 28982739 PMCID: PMC5897187 DOI: 10.1136/gutjnl-2016-313372] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 08/18/2017] [Accepted: 08/21/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC). DESIGN Genome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy. RESULTS Methylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1% and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival. CONCLUSION This five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.
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Affiliation(s)
- Ludovic Barault
- Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Corresponding authors: Ludovic Barault, PhD or Dr Federica Di Nicolantonio, PhD, Department of Oncology, University of Torino, Candiolo Cancer Institute – FPO, IRCCS, Strada Provinciale 142, Km 3.95, 10060 Candiolo, Torino, Italy, Phone: +39-011-9933523, Fax: +39-011-9933225, (; )
| | - Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giulia Siravegna
- Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy,FIRC Institute of Molecular Oncology (IFOM), Milano, Italy
| | - Agostino Ponzetti
- Colorectal Cancer Unit, Medical Oncology Division 1, AOU Città della Salute e della Scienza, San Giovanni Battista Hospital, Turin, Italy
| | - Sebastian Moran
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L’Hospitalet, Barcelona, Catalonia, Spain
| | - Andrea Cassingena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Benedetta Mussolin
- Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy
| | - Chiara Falcomatà
- Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy
| | - Alexandra Binder
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, USA
| | - Carmen Cristiano
- Colorectal Cancer Unit, Medical Oncology Division 1, AOU Città della Salute e della Scienza, San Giovanni Battista Hospital, Turin, Italy
| | - Daniele Oddo
- Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy
| | - Carlotta Cancelliere
- Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy
| | - Sara Bustreo
- Colorectal Cancer Unit, Medical Oncology Division 1, AOU Città della Salute e della Scienza, San Giovanni Battista Hospital, Turin, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Sean Maden
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Alice Vanzati
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Patrizia Zavattari
- Unit of Biology and Genetics, Dept. Biomedical Sciences, University of Cagliari, Italy
| | - Mauro Truini
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA,Department of Medicine, University of Washington School of Medicine, Seattle, WA
| | - Patrizia Racca
- Colorectal Cancer Unit, Medical Oncology Division 1, AOU Città della Salute e della Scienza, San Giovanni Battista Hospital, Turin, Italy
| | - Karin B. Michels
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, USA
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy,Università degli Studi di Milano, Milan, Italy
| | - Manel Esteller
- Colorectal Cancer Unit, Medical Oncology Division 1, AOU Città della Salute e della Scienza, San Giovanni Battista Hospital, Turin, Italy,Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain,Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
| | - Alberto Bardelli
- Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy
| | | | - Federica Di Nicolantonio
- Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Candiolo Cancer Institute-FPO, IRCCS, SP 142 km 3.95, 10060 Candiolo (TO), Italy,Corresponding authors: Ludovic Barault, PhD or Dr Federica Di Nicolantonio, PhD, Department of Oncology, University of Torino, Candiolo Cancer Institute – FPO, IRCCS, Strada Provinciale 142, Km 3.95, 10060 Candiolo, Torino, Italy, Phone: +39-011-9933523, Fax: +39-011-9933225, (; )
| | | | - Federica Di Nicolantonio
- Department of Oncology, University of Torino, Torino, Italy.,Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
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Chen JC, Huang C, Lee IN, Wu YP, Tang CH. Amphiregulin enhances cell migration and resistance to doxorubicin in chondrosarcoma cells through the MAPK pathway. Mol Carcinog 2018; 57:1816-1824. [DOI: 10.1002/mc.22899] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 08/24/2018] [Accepted: 08/31/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Jui-Chieh Chen
- Department of Biochemical Science and Technology; National Chiayi University; Chiayi City Taiwan
| | - Cheng Huang
- Department of Biotechnology and Laboratory Science in Medicine; National Yang-Ming University; Taipei Taiwan
- Department of Earth and Life Sciences; University of Taipei; Taipei Taiwan
| | - I-Neng Lee
- Department of Medical Research; Chang Gung Memorial Hospital; Chiayi Taiwan
| | - Yu-Ping Wu
- Department of Biochemical Science and Technology; National Chiayi University; Chiayi City Taiwan
- Department of Medical Research; Chang Gung Memorial Hospital; Chiayi Taiwan
| | - Chih-Hsin Tang
- Department of Pharmacology; School of Medicine; China Medical University; Taichung Taiwan
- Chinese Medicine Research Center; China Medical University; Taichung Taiwan
- Department of Biotechnology; College of Medical and Health Science; Asia University; Taichung Taiwan
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43
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Khan KH, Cunningham D, Werner B, Vlachogiannis G, Spiteri I, Heide T, Mateos JF, Vatsiou A, Lampis A, Damavandi MD, Lote H, Huntingford IS, Hedayat S, Chau I, Tunariu N, Mentrasti G, Trevisani F, Rao S, Anandappa G, Watkins D, Starling N, Thomas J, Peckitt C, Khan N, Rugge M, Begum R, Hezelova B, Bryant A, Jones T, Proszek P, Fassan M, Hahne JC, Hubank M, Braconi C, Sottoriva A, Valeri N. Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial. Cancer Discov 2018; 8:1270-1285. [PMID: 30166348 PMCID: PMC6380469 DOI: 10.1158/2159-8290.cd-17-0891] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 05/01/2018] [Accepted: 07/05/2018] [Indexed: 12/14/2022]
Abstract
Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies.Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270-85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213 This article is highlighted in the In This Issue feature, p. 1195.
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Affiliation(s)
- Khurum H Khan
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - David Cunningham
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Benjamin Werner
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - Georgios Vlachogiannis
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Inmaculada Spiteri
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - Timon Heide
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - Javier Fernandez Mateos
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - Alexandra Vatsiou
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
| | - Andrea Lampis
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Mahnaz Darvish Damavandi
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Hazel Lote
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Ian Said Huntingford
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Somaieh Hedayat
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Ian Chau
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Nina Tunariu
- Department of Radiology, The Royal Marsden NHS Trust, Londonand Sutton, United Kingdom
| | - Giulia Mentrasti
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Francesco Trevisani
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Sheela Rao
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Gayathri Anandappa
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - David Watkins
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Naureen Starling
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Janet Thomas
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Clare Peckitt
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Nasir Khan
- Department of Radiology, The Royal Marsden NHS Trust, Londonand Sutton, United Kingdom
| | - Massimo Rugge
- Department of Medicine and Surgical Pathology, University of Padua, Padua, Italy
| | - Ruwaida Begum
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Blanka Hezelova
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Annette Bryant
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Thomas Jones
- Clinical Genomics, The Centre for Molecular Pathology, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Paula Proszek
- Clinical Genomics, The Centre for Molecular Pathology, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Matteo Fassan
- Department of Medicine and Surgical Pathology, University of Padua, Padua, Italy
| | - Jens C Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Michael Hubank
- Clinical Genomics, The Centre for Molecular Pathology, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
| | - Chiara Braconi
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom
- Division of Cancer Therapeutics, The Institute of Cancer Research, London and Sutton, United Kingdom
| | - Andrea Sottoriva
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.
| | - Nicola Valeri
- Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.
- Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom
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44
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Hyrenius-Wittsten A, Pilheden M, Sturesson H, Hansson J, Walsh MP, Song G, Kazi JU, Liu J, Ramakrishan R, Garcia-Ruiz C, Nance S, Gupta P, Zhang J, Rönnstrand L, Hultquist A, Downing JR, Lindkvist-Petersson K, Paulsson K, Järås M, Gruber TA, Ma J, Hagström-Andersson AK. De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia. Nat Commun 2018; 9:1770. [PMID: 29720585 PMCID: PMC5932012 DOI: 10.1038/s41467-018-04180-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 04/11/2018] [Indexed: 02/07/2023] Open
Abstract
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRASG12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the KrasG12D locus, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver. In acute leukemia with KMT2A rearrangements (KMT2A-R), activating signaling mutations are common. Here, the authors use a retroviral acute myeloid mouse leukemia model to show that subclonal de novo activating mutations drive clonal evolution in acute leukemia with KMT2A-R and enhance clonal fitness.
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Affiliation(s)
- Axel Hyrenius-Wittsten
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Mattias Pilheden
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Helena Sturesson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Jenny Hansson
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Michael P Walsh
- Department of Pathology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Guangchun Song
- Department of Pathology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Julhash U Kazi
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 223 63, Lund, Sweden
| | - Jian Liu
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Ramprasad Ramakrishan
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Cristian Garcia-Ruiz
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Stephanie Nance
- Department of Oncology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Pankaj Gupta
- Department of Computational Biology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Jinghui Zhang
- Department of Computational Biology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Lars Rönnstrand
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 223 63, Lund, Sweden.,Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.,Division of Oncology, Skane University Hospital, Lund University, 221 85, Lund, Sweden
| | - Anne Hultquist
- Department of Pathology, Skane University Hospital, Lund University, 221 85, Lund, Sweden
| | - James R Downing
- Department of Pathology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Karin Lindkvist-Petersson
- Medical Structural Biology, Department of Experimental Medical Science, 221 84 Lund University, Lund, Sweden
| | - Kajsa Paulsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Marcus Järås
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden
| | - Tanja A Gruber
- Department of Pathology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA.,Department of Oncology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Jing Ma
- Department of Pathology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA
| | - Anna K Hagström-Andersson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
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Mésange P, Bouygues A, Ferrand N, Sabbah M, Escargueil AE, Savina A, Chibaudel B, Tournigand C, André T, de Gramont A, Larsen AK. Combinations of Bevacizumab and Erlotinib Show Activity in Colorectal Cancer Independent of RAS Status. Clin Cancer Res 2018; 24:2548-2558. [PMID: 29490990 DOI: 10.1158/1078-0432.ccr-17-3187] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/09/2018] [Accepted: 02/20/2018] [Indexed: 11/16/2022]
Abstract
Purpose: There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant RAS Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib.Experimental Design: The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR-EGF ligand feedback loop was established in colorectal cancer cell lines with different RAS status.Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wild-type cells.Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab-erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. Clin Cancer Res; 24(11); 2548-58. ©2018 AACR.
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Affiliation(s)
- Paul Mésange
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Anaïs Bouygues
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Nathalie Ferrand
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Michèle Sabbah
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France.,Centre National de la Recherche Scientifique (CNRS), Paris, France
| | - Alexandre E Escargueil
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France
| | - Ariel Savina
- Roche Scientific Partnerships, Boulogne-Billancourt, France
| | - Benoist Chibaudel
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Department of Medical Oncology, Institut Hospitalier Franco-Britannique, Levallois-Perret, France
| | - Christophe Tournigand
- Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France.,Université Paris Est, Créteil, France
| | - Thierry André
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France.,Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
| | - Aimery de Gramont
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Department of Medical Oncology, Institut Hospitalier Franco-Britannique, Levallois-Perret, France
| | - Annette K Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France. .,Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.,Institut Universitaire de Cancérologie (IUC), Faculté de Médecine, Sorbonne Université, Paris, France.,Centre National de la Recherche Scientifique (CNRS), Paris, France
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46
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A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors. Oncotarget 2018; 7:72167-72183. [PMID: 27708224 PMCID: PMC5342152 DOI: 10.18632/oncotarget.12354] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 09/21/2016] [Indexed: 12/13/2022] Open
Abstract
Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes. In this study, we employed a colon cancer model to assess potential mechanisms driving resistance to cetuximab. Resistant cells displayed increased ability to grow in suspension as colonspheres and this phenotype was associated with poorly organized structures. Factors secreted from resistant cells were causally involved in sustaining resistance, indeed administration to parental cells of conditioned medium collected from resistant cells was sufficient to reduce cetuximab efficacy. Among secreted factors, we report herein that a signature of inflammatory cytokines, including IL1A, IL1B and IL8, which are produced following EGFR pathway activation, was associated with the acquisition of an unresponsive phenotype to cetuximab in vitro. This signature correlated with lack of response to EGFR targeting also in patient-derived tumour xenografts. Collectively, these results highlight the contribution of inflammatory cytokines to reduced sensitivity to EGFR blockade and suggest that inhibition of this panel of cytokines in combination with cetuximab might yield an effective treatment strategy for CRC patients refractory to anti-EGFR targeting.
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Gambara G, Gaebler M, Keilholz U, Regenbrecht CRA, Silvestri A. From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity. Front Pharmacol 2018; 9:77. [PMID: 29491834 PMCID: PMC5817069 DOI: 10.3389/fphar.2018.00077] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/23/2018] [Indexed: 12/15/2022] Open
Abstract
Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH) for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (micro)environment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D) cell cultures and patient-derived tumor xenografts (PDX) as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue.
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Affiliation(s)
- Guido Gambara
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin, Berlin, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Manuela Gaebler
- Department of Interdisciplinary Oncology, HELIOS Klinikum Berlin-Buch GmbH, Berlin, Germany
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin, Berlin, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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48
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Jing C, Jin YH, You Z, Qiong Q, Jun Z. Prognostic value of amphiregulin and epiregulin mRNA expression in metastatic colorectal cancer patients. Oncotarget 2018; 7:55890-55899. [PMID: 27344184 PMCID: PMC5342459 DOI: 10.18632/oncotarget.10151] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 06/06/2016] [Indexed: 12/22/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) and its ligands amphiregulin (AREG) and epiregulin (EREG) play a central role in the development of colorectal cancer, but the prognostic values of AREG and EREG are controversial. We conducted a meta-analysis of studies that investigated AREG and/or EREG mRNA levels in primary tumors to determine their prognostic value in metastatic colorectal cancer (mCRC). In addition, RAS status was assessed. Relevant articles were identified by searching the EMBASE, PubMed, and Cochrane Library databases. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Nine studies involving 2167 patients were included in this meta-analysis. High AREG expression was associated with longer overall survival (OS) and progression-free survival (PFS). High EREG expression was also associated with prolonged OS and PFS. In RAS wild-type (WT) patients who received anti-EGFR therapy, high AREG and EREG expression was associated with longer OS. Our results indicate that high AREG and EREG mRNA expression are independent favorable prognostic biomarkers in mCRC. The expression of these ligands should be considered when evaluating prognoses in RAS-WT patients receiving anti-EGFR therapy.
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Affiliation(s)
- Chen Jing
- Department of Medical Oncology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Yang Han Jin
- Department of Pathology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Zhai You
- Department of Pharmacy, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Qian Qiong
- Department of Medical Oncology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Zhou Jun
- Department of Pharmacy, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
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Liu Y, Wang SQ, Long YH, Chen S, Li YF, Zhang JH. KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway. Oncotarget 2018; 7:53153-53164. [PMID: 27449290 PMCID: PMC5288175 DOI: 10.18632/oncotarget.10625] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 07/06/2016] [Indexed: 11/25/2022] Open
Abstract
It remains unclear how the signals of mutant KRASG12 in the transformed cells spread to the surrounding non-mutated cells and changes the microenvironment to promote tumor formation. We identified that Williams–Beuren syndrome transcription factor (WSTF), a non-secretory protein, was released in complex with secretory protein-neuregulin-3 (NRG3). The KRASG12 mutant activates the transcription of NRG3. The WSTF/NRG3 in extracellular space could activate oncogenic pathways in normal colon cells carrying wild type KRAS and endow them with the ability to express NRG3 and release WSTF/NRG3. Extracellular WSTF/NRG3 promotes the formation of colon tumors. Blockade of extracellular WSTF could restore cetuximab sensitivity of colon cancer cells with mutant KRAS. The appearance of WSTF/NRG3 in serum and urine correlates with a colon tumor carrying a KRASG12 mutant. In summary, our demonstration provides a new pathway to our understanding of the biological development of complex diseases.
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Affiliation(s)
- Yan Liu
- College of Life Science, North China University of Science and Technology, Tangshan, 063000, China.,Cancer Institute, Tangshan People's Hospital, Tangshan, 063001, China
| | - Shu-Qing Wang
- Hospital of The North China University of Science and Technology, Tangshan, 063000, China.,Department of Nephrology, Affiliated Kailuan General Hospital of North China University of Science and Technology, Tangshan, 063000, China
| | - Yue-Hong Long
- College of Life Science, North China University of Science and Technology, Tangshan, 063000, China
| | - Su Chen
- School of Life Sciences and Technology, Department of Breast Surgery of Yangpu Hospital, Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200092, China
| | - Yu-Feng Li
- Cancer Institute, Tangshan People's Hospital, Tangshan, 063001, China
| | - Jing-Hua Zhang
- Cancer Institute, Tangshan People's Hospital, Tangshan, 063001, China
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50
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Yun S, Kwak Y, Nam SK, Seo AN, Oh HK, Kim DW, Kang SB, Lee HS. Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer. Cancer Res Treat 2018; 50:1351-1361. [PMID: 29361822 PMCID: PMC6192927 DOI: 10.4143/crt.2017.487] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 01/15/2018] [Indexed: 12/14/2022] Open
Abstract
Purpose Molecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients’ survival with CRC. Materials and Methods The expression of EGFR ligands, including heparin binding epidermal growth factor-like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH. Results Unlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands‒/EGFR+ group showed a significant association with the worst disease-free survival (DFS; p=0.018) and overall survival (OS; p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis. Conclusion Ligand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.
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Affiliation(s)
- Sumi Yun
- Department of Diagnostic Pathology, Samkwang Medical Laboratories, Seoul, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - An Na Seo
- Department of Pathology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Heung-Kwon Oh
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Duck-Woo Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sung-Bum Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
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