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Yu L, Zhang C, Liu L, Chen X. Effects of immunorelated gene polymorphisms on trastuzumab targeting breast cancer cell in vitro. Pharmacogenomics 2024; 25:461-468. [PMID: 39392082 PMCID: PMC11492633 DOI: 10.1080/14622416.2024.2404819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 09/12/2024] [Indexed: 10/12/2024] Open
Abstract
Aim: To investigate the associations between genetic polymorphisms in immunorelated genes and PBMC-induced cytotoxicity to breast cancer cell with the treatment of trastuzumab in vitro.Methods: Trastuzumab-mediated cytotoxicity of peripheral blood mononuclear cells (PBMC) from 148 healthy donors and 13 BC patients was analyzed by flow cytometry. 16 SNPs in 7 immunorelated genes were genotyped by Sequenom Mass Array Genotype Platform.Results: Cytotoxicity in the trastuzumab treated PBMCs were significantly higher than those of the basal group. A wide variability in trastuzumab-mediated cytotoxicity was observed, and PBMC from individuals with the CD247 rs16859030 T genotype generated increased cytotoxicity than those with the CC genotype.Conclusion: The CD247 rs16859030 polymorphism affects trastuzumab-mediated cytotoxicity in vitro.
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Affiliation(s)
- Linyu Yu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Congmin Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Liangyu Liu
- Office of drug clinical trial institution, Ganzhou People's Hospital, Ganzhou, 341000, China
| | - Xiaoping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
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2
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Wu D, Pan C, Hu Y, Shi Z, Zhou Y, Xiao M. A bibliometric and visualization analysis of research trends and hotspots on targeted therapy for breast cancer from 2003 to 2022. Front Oncol 2024; 14:1366900. [PMID: 38894873 PMCID: PMC11183788 DOI: 10.3389/fonc.2024.1366900] [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: 03/04/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Background Breast cancer is a significant public health issue, exhibiting the most pronounced occurrence and fatality rates among malignant neoplasms globally. Targeted therapy is a medical intervention that focuses on specific molecular markers. This study aims to investigate and evaluate the current research trends and directions in the field of targeted therapy for breast cancer using bibliometric analysis. Method The Web of Science database was utilized to retrieve relevant articles published between 2003 and 2022. The VOSviewer software and Bibliometrix package in the R language were employed to conduct co-occurrence and clustering analyses of authors, countries, institutions, journals, references, and the CiteSpace tool was utilized for keyword burst detection. Results A total of 2,258 articles were included and the annual number of publications increased rapidly. The most prolific country on this topic was the USA (n=898, 39.77%) and the University of Texas MD Anderson Cancer Center published most papers (n=93). Dennis J. Slamon and Gabriel N. Hortobagyi stood out in the field, with Dennis J. Slamon leading in terms of co-citations(n=653) and Gabriel N. Hortobagyi topping the list in terms of published articles(n=18). The most productive journal was Breast Cancer Research and Treatment and the most cited journal was Journal of Clinical Oncology. The clustering of keywords indicated that the primary focus of researches in the past two decades was on the development and clinical evaluation of tumor-targeted drugs associated with the epidermal growth factor receptor (EGFR) family signaling pathway, and explored mechanisms related to biological behavior of breast cancer. Keywords co-occurrence and burst analysis identified current research hotspots and potential research trends. Conclusion This study employed bibliometric analysis to examine research on targeted therapy for breast cancer over a span of 20 years, and identified development trends of research and elucidated potential research trajectories in the domain of this topic. This study helps in the identification of prospective collaborators and partner institutions for researchers.
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Affiliation(s)
- Deqi Wu
- Department of Thyroid and Breast Diagnosis and Treatment Center, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Chi Pan
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yangying Hu
- Department of Thyroid and Breast Diagnosis and Treatment Center, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Zhijie Shi
- Department of Thyroid and Breast Diagnosis and Treatment Center, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yankun Zhou
- Zhejiang University School of Medicine, Hangzhou, China
| | - Min Xiao
- Department of Surgery, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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3
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Zhao S, Qiu Y, Yuan M, Wang Z. Progress of PD-1/PD-L1 inhibitor combination therapy in immune treatment for HER2-positive tumors. Eur J Clin Pharmacol 2024; 80:625-638. [PMID: 38342825 DOI: 10.1007/s00228-024-03644-2] [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: 09/24/2023] [Accepted: 02/02/2024] [Indexed: 02/13/2024]
Abstract
BACKGROUND Patients with HER2-positive cancers often face a poor prognosis, and treatment regimens containing anti-HER2 have become the first-line treatment options for breast and gastric cancers. However, these approaches are faced with significant challenges in terms of drug resistance. Hence, it is crucial to explore precise treatment strategies aimed at improving survival outcomes. ADVANCEMENTS IN TREATMENT Over the past few years, there has been rapid advancement in the realm of tumor therapy, particularly with the swift progress of immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors. They exert anti-tumor effects by disrupting immune-suppressive factors within the tumor microenvironment. However, monotherapy with PD-1/PD-L1 inhibitors has several limitations. Consequently, numerous studies have explored combinatorial immunotherapeutic strategies and demonstrated highly promising avenues of development. OBJECTIVE This article aims to review the clinical trials investigating PD-1/PD-L1 inhibitor combination therapy for HER2-positive tumors. Additionally, it provides a summary of ongoing trials evaluating the efficacy and safety of these combined treatments, with the intention of furnishing valuable insights for the clinical management of HER2-positive cancer. CONCLUSION Combinatorial immunotherapeutic strategies involving PD-1/PD-L1 inhibitors hold considerable promise in the treatment of HER2-positive tumors. Continued research efforts and clinical trials are warranted to elucidate optimal treatment regimens that maximize therapeutic benefits while minimizing adverse effects.
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Affiliation(s)
- Sining Zhao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yiwu Qiu
- School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Meiqin Yuan
- Department of Colorectal Medicine, Zhejiang Cancer Hospital, Hangzhou, China
| | - Zeng Wang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, China, 310022.
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4
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Wang Y, Peng X, Wu M, Wang B, Chen T, Zhan X. SLC35A2 expression is associated with HER2 expression in breast cancer. Discov Oncol 2024; 15:124. [PMID: 38639872 PMCID: PMC11031507 DOI: 10.1007/s12672-024-00978-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 04/09/2024] [Indexed: 04/20/2024] Open
Abstract
The role of SLC35A2 in breast cancer remains poorly understood, with limited available information on its significance. This study aimed to investigate the expression of SLC35A2 and clinicopathological variables in breast cancer patients. Immunohistochemical analysis of SLC35A2 protein was conductedon 40 adjacent non-neoplastic tissues and 320 breast cancer tissues. The study also assesed the association between SLC35A2 expression and breast cancer clinicopathological features of breast cancer, as well as its impact on overall survival. In comparison to adjacent non-neoplastic tissues, a significantly higher expression of SLC35A2 was observed in breast cancer tissues (P = 0.020), and this expression was found to be independently correlated with HER2 positivity (P = 0.001). Survival analysis indicated that patients with low SLC35A2 expression had a more favorable prognosis in HER2-positive subtype breast cancer (P = 0.017). These results suggest that SLC35A2 is overexpressed in breast cancer tissues compared to adjacent non-neoplastic tissues and may serve as a potential prognostic marker for HER2-positive subtype breast cancer. Furthermore, breast cancer patients with the HER2 positive subtype who exhibited decreased levels of SLC35A2 expression demonstrated improved long-term prognostic outcomes.
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Affiliation(s)
- Yiran Wang
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xiaobo Peng
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Meihong Wu
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Bin Wang
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Tianran Chen
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xianbao Zhan
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
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Guo Y, Li X, Xie Y, Wang Y. What influences the activity of Degrader-Antibody conjugates (DACs). Eur J Med Chem 2024; 268:116216. [PMID: 38387330 DOI: 10.1016/j.ejmech.2024.116216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/23/2024] [Accepted: 02/01/2024] [Indexed: 02/24/2024]
Abstract
The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for the treatment of cancer and other diseases. PROTACs have demonstrated significant advantages in targeting undruggable targets and overcoming drug resistance. However, despite the efficient degradation of targeted proteins achieved by PROTACs, they still face challenges related to selectivity between normal and cancer cells, as well as issues with poor membrane permeability due to their substantial molecular weight. Additionally, the noteworthy toxicity resulting from off-target effects also needs to be addressed. To solve these issues, Degrader-Antibody Conjugates (DACs) have been developed, leveraging the targeting and internalization capabilities of antibodies. In this review, we elucidates the characteristics and distinctions between DACs, and traditional Antibody-drug conjugates (ADCs). Meanwhile, we emphasizes the significance of DACs in facilitating the delivery of PROTACs and delves into the impact of various components on DAC activity. These components include antibody targets, drug-antibody ratio (DAR), linker types, PROTACs targets, PROTACs connections, and E3 ligase ligands. The review also explores the suitability of different targets (antibody targets or PROTACs targets) for DACs, providing insights to guide the design of PROTACs better suited for antibody conjugation.
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Affiliation(s)
- Yaolin Guo
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China
| | - Xiaoxue Li
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yang Xie
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China
| | - Yuxi Wang
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China.
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6
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Sombal W, Khan NU, Khan BM, Ismail M, Almutairi MH, Khan S, Khan AU, Mustafa A, Iftikhar B, Ali I. Human epidermal growth receptor polymorphisms ( HER1-rs11543848 and HER2-rs1136201) exhibited significant association with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan. Health Sci Rep 2024; 7:e1846. [PMID: 38317673 PMCID: PMC10839356 DOI: 10.1002/hsr2.1846] [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: 10/14/2023] [Revised: 12/09/2023] [Accepted: 01/08/2024] [Indexed: 02/07/2024] Open
Abstract
Background and Aims Breast cancer is the most common type of cancer in women. The genetic polymorphism in HER (HER1-rs11543848 and HER2-rs1136201) were found to be associated with breast cancer risk in different ethnicities worldwide with inconsistent results. The aim of this research study was to evaluate the association of HER1-rs11543848 and HER2-rs1136201 polymorphisms as a risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. Methods A total of 314 women including 164 breast cancer patients and 150 age and gender-matched healthy controls were enrolled from June 2021 to May 2022. All the samples were subjected to DNA extraction followed by Tetra-ARMS-PCR for genotyping and gel electrophoresis. Results Our results indicated that HER1-rs11543848 risk allele A (p = 0.0001) and heterozygous genotype GA (p = 0.0001) displayed highly significant association with breast cancer, while the homozygous mutant genotype AA indicated association but nonsignificant results (odds ratio [OR] = 2.637, 95% confidence interval [CI] = 1.2258-5.6756, p = 0.0833). Similarly, the HER2-rs1136201 risk allele G (p = 0.0023), the heterozygous genotype AG (p = 0.0530) and homozygous mutant genotype GG showed significant association (OR = 2.5946, 95% CI = 0.9876-6.8165, p = 0.0530) with breast cancer risk. Both the SNPs presented a higher but nonsignificant risk of breast cancer in postmenopausal women (OR = 2.242, p = 0.08 and OR = 2.009, p = 0.06). However, both the SNPs showed significant association (p < 0.005) with family history, metastasis, stage, luminal B, and TNBC. Conclusion In conclusion, HER1-rs11543848 and HER2-rs1136201 polymorphisms are significantly associated with the higher risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. These findings advocate for further exploration with larger datasets, offering promising avenues for personalized approaches in breast cancer research and potentially enhancing clinical practices for better risk assessment and targeted management strategies.
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Affiliation(s)
- Wafa Sombal
- Institute of Biotechnology & Genetic Engineering (Health Division)The University of Agriculture PeshawarPeshawarPakistan
| | - Najeeb Ullah Khan
- Institute of Biotechnology & Genetic Engineering (Health Division)The University of Agriculture PeshawarPeshawarPakistan
| | - Bibi Maryam Khan
- School of Life ScienceJiangsu UniversityZhejiangJiangsu ProvincePeople's Republic of China
| | | | | | - Samiullah Khan
- Institute of Radiotherapy and Nuclear Medicine (IRNUM)PeshawarPakistan
| | - Aakif Ullah Khan
- Institute of Radiotherapy and Nuclear Medicine (IRNUM)PeshawarPakistan
| | - Adeela Mustafa
- Department of Community MedicineKhyber Medical CollegePeshawarPakistan
| | - Bushra Iftikhar
- Department of Community MedicineKhyber Medical CollegePeshawarPakistan
| | - Ijaz Ali
- Centre for Applied Mathematics and Bioinformatics (CAMB)Gulf University for Science and TechnologyHawallyKuwait
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Fernandes CL, Silva DJ, Mesquita A. Novel HER-2 Targeted Therapies in Breast Cancer. Cancers (Basel) 2023; 16:87. [PMID: 38201515 PMCID: PMC10778064 DOI: 10.3390/cancers16010087] [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: 11/18/2023] [Revised: 12/13/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Human epidermal growth factor 2 (HER-2)-positive breast cancer represents 15-20% of all breast cancer subtypes and has an aggressive biological behavior with worse prognosis. The development of HER-2-targeted therapies has changed the disease's course, having a direct impact on survival rates and quality of life. Drug development of HER-2-targeting therapies is a prolific field, with numerous new therapeutic strategies showing survival benefits and gaining regulatory approval in recent years. Furthermore, the acknowledgement of the survival impact of HER-2-directed therapies on HER-2-low breast cancer has contributed even more to advances in the field. The present review aims to summarize the newly approved therapeutic strategies for HER-2-positive breast cancer and review the new and exploratory HER-2-targeted therapies currently under development.
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Affiliation(s)
- Catarina Lopes Fernandes
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal; (D.J.S.); (A.M.)
| | - Diogo J. Silva
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal; (D.J.S.); (A.M.)
| | - Alexandra Mesquita
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal; (D.J.S.); (A.M.)
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
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8
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Adam-Artigues A, Arenas EJ, Arribas J, Prat A, Cejalvo JM. AXL - a new player in resistance to HER2 blockade. Cancer Treat Rev 2023; 121:102639. [PMID: 37864955 DOI: 10.1016/j.ctrv.2023.102639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/03/2023] [Accepted: 10/06/2023] [Indexed: 10/23/2023]
Abstract
HER2 is a driver in solid tumors, mainly breast, oesophageal and gastric cancer, through activation of oncogenic signaling pathways such as PI3K or MAPK. HER2 overexpression associates with aggressive disease and poor prognosis. Despite targeted anti-HER2 therapy has improved outcomes and is the current standard of care, resistance emerge in some patients, requiring additional therapeutic strategies. Several mechanisms, including the upregulation of receptors tyrosine kinases such as AXL, are involved in resistance. AXL signaling leads to cancer cell proliferation, survival, migration, invasion and angiogenesis and correlates with poor prognosis. In addition, AXL overexpression accompanied by a mesenchymal phenotype result in resistance to chemotherapy and targeted therapies. Preclinical studies show that AXL drives anti-HER2 resistance and metastasis through dimerization with HER2 and activation of downstream pathways in breast cancer. Moreover, AXL inhibition restores response to HER2 blockade in vitro and in vivo. Limited data in gastric and oesophageal cancer also support these evidences. Furthermore, AXL shows a strong value as a prognostic and predictive biomarker in HER2+ breast cancer patients, adding a remarkable translational relevance. Therefore, current studies enforce the potential of co-targeting AXL and HER2 to overcome resistance and supports the use of AXL inhibitors in the clinic.
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Affiliation(s)
| | - Enrique J Arenas
- Josep Carreras Leukaemia Research Institute, Spain; Center for Biomedical Network Research on Cancer (CIBERONC), Spain.
| | - Joaquín Arribas
- Center for Biomedical Network Research on Cancer (CIBERONC), Spain; Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Spain; Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Spain; Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Spain.
| | - Aleix Prat
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Spain; Department of Medical Oncology, Hospital Clínic de Barcelona, Spain; SOLTI Breast Cancer Research Group, Spain.
| | - Juan Miguel Cejalvo
- INCLIVA Biomedical Research Institute, Spain; Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Spain; Department of Medical Oncology, Hospital Clínico Universitario de València, Spain.
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9
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Gutjahr E, Fremd C, Arnscheidt J, Penzel R, Wacker J, Sinn P. Non-Response of Epstein-Barr Virus-Associated Breast Cancer after Primary Chemotherapy: Report of Two Cases. Pathogens 2023; 12:1387. [PMID: 38133273 PMCID: PMC10747629 DOI: 10.3390/pathogens12121387] [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: 09/19/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023] Open
Abstract
Based on epidemiological evidence and molecular findings, a possible association of Epstein-Barr virus (EBV) with the carcinogenesis of breast cancer has been described. However, the frequency of EBV in breast cancer and the role of EBV regarding tumor progression or therapeutic results is largely unexplored. Here, we report on two cases of advanced, lymph node-positive invasive breast cancer of no special type (NST), histologically showing no clinical or histological evidence of tumor regression as an equivalent of a lack of response to primary systemic therapy. Both tumors were considered to be EBV-associated due to their positivity in EBV-encoded RNA (EBER) in situ hybridization (ISH) and their immunoreactivity against EBV Epstein-Barr nuclear antigen 1 (EBNA1). We hypothesize that the unusual non-response to chemotherapy in these cases of breast cancer classified as triple-negative and HER2-positive may be linked to the EBV co-infection of tumor cells. Therefore, EBV tumor testing should be considered in patients with breast cancer presenting with resistance to chemotherapy. This hypothesis may provide a new aspect in the context of EBV-associated mechanisms of tumor progression.
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Affiliation(s)
- Ewgenija Gutjahr
- Department of General Pathology, University Hospital, 69121 Heidelberg, Germany
| | - Carlo Fremd
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital and German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany
| | - Johanna Arnscheidt
- Department of General Pathology, University Hospital, 69121 Heidelberg, Germany
| | - Roland Penzel
- Department of General Pathology, University Hospital, 69121 Heidelberg, Germany
| | - Jürgen Wacker
- Department of Obstetrics and Gynecology, Fuerst-Stirum-Hospital, 76646 Bruchsal, Germany
| | - Peter Sinn
- Department of General Pathology, University Hospital, 69121 Heidelberg, Germany
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10
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He Y, Goyette MA, Chapelle J, Boufaied N, Al Rahbani J, Schonewolff M, Danek EI, Muller WJ, Labbé DP, Côté JF, Lamarche-Vane N. CdGAP is a talin-binding protein and a target of TGF-β signaling that promotes HER2-positive breast cancer growth and metastasis. Cell Rep 2023; 42:112936. [PMID: 37552602 DOI: 10.1016/j.celrep.2023.112936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 05/10/2023] [Accepted: 07/20/2023] [Indexed: 08/10/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. Here, we show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor β (TGF-β)-induced EMT transcriptional signature. CdGAP is positively regulated by TGF-β signaling during EMT and interacts with the adaptor talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-β-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-β and integrin/talin signaling pathways.
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Affiliation(s)
- Yi He
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Marie-Anne Goyette
- Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, QC H2W 1R7, Canada
| | - Jennifer Chapelle
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Nadia Boufaied
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
| | - Jalal Al Rahbani
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Maribel Schonewolff
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - Eric I Danek
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada
| | - William J Muller
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada
| | - David P Labbé
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Division of Urology, Department of Surgery, McGill University, Montréal, QC H4A 3J1, Canada
| | - Jean-François Côté
- Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada; Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, QC H2W 1R7, Canada
| | - Nathalie Lamarche-Vane
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada.
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11
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Najminejad Z, Dehghani F, Mirzaei Y, Mer AH, Saghi SA, Abdolvahab MH, Bagheri N, Meyfour A, Jafari A, Jahandideh S, Gharibi T, Amirkhani Z, Delam H, Mashatan N, Shahsavarani H, Abdollahpour-Alitappeh M. Clinical perspective: Antibody-drug conjugates for the treatment of HER2-positive breast cancer. Mol Ther 2023; 31:1874-1903. [PMID: 36950736 PMCID: PMC10362395 DOI: 10.1016/j.ymthe.2023.03.019] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 01/31/2023] [Accepted: 03/16/2023] [Indexed: 03/24/2023] Open
Abstract
Antibody-drug conjugates (ADCs) are a promising class of cancer biopharmaceuticals that exploit the specificity of a monoclonal antibody (mAb) to selectively deliver highly cytotoxic small molecules to targeted cancer cells, leading to an enhanced therapeutic index through increased antitumor activity and decreased off-target toxicity. ADCs hold great promise for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer after the approval and tremendous success of trastuzumab emtansine and trastuzumab deruxtecan, representing a turning point in both HER2-positive breast cancer treatment and ADC technology. Additionally and importantly, a total of 29 ADC candidates are now being investigated in different stages of clinical development for the treatment of HER2-positive breast cancer. The purpose of this review is to provide an insight into the ADC field in cancer treatment and present a comprehensive overview of ADCs approved or under clinical investigation for the treatment of HER2-positive breast cancer.
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Affiliation(s)
- Zohreh Najminejad
- Department of Internal Medicine, School of Medicine, Kerman University of Medical Sciences, Kerman 7616913355, Iran
| | - Fatemeh Dehghani
- Student Research Committee, Larestan University of Medical Sciences, Larestan 7431895639, Iran
| | - Yousef Mirzaei
- Department of Medical Biochemical Analysis, Cihan University-Erbil, Kurdistan Region, Erbil 44001, Iraq
| | - Ali Hussein Mer
- Department of Nursing, Mergasour Technical Institute, Erbil Polytechnic University, Erbil 44001, Iraq
| | - Seyyed Amirreza Saghi
- Student Research Committee, Larestan University of Medical Sciences, Larestan 7431895639, Iran
| | - Mohadeseh Haji Abdolvahab
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1517964311, Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8813733450, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Ameneh Jafari
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1517964311, Iran
| | - Saeed Jahandideh
- Department of Research and Development, Orchidgene co, Tehran 1387837584, Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran
| | - Zahra Amirkhani
- Student Research Committee, Larestan University of Medical Sciences, Larestan 7431895639, Iran
| | - Hamed Delam
- Student Research Committee, Larestan University of Medical Sciences, Larestan 7431895639, Iran
| | - Noushin Mashatan
- Graduated, School of Applied Sciences, University of Brighton, Brighton BN2 4GJ, UK.
| | - Hosein Shahsavarani
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran 1983963113, Iran.
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12
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Zhang XN, Gao Y, Zhang XY, Guo NJ, Hou WQ, Wang SW, Zheng YC, Wang N, Liu HM, Wang B. Detailed curriculum vitae of HER2-targeted therapy. Pharmacol Ther 2023; 245:108417. [PMID: 37075933 DOI: 10.1016/j.pharmthera.2023.108417] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
With the booming development of precision medicine, molecular targeted therapy has been widely used in clinical oncology treatment due to a smaller number of side effects and its superior accuracy compared to that of traditional strategies. Among them, human epidermal growth factor receptor 2 (HER2)-targeted therapy has attracted considerable attention and has been used in the clinical treatment of breast and gastric cancer. Despite excellent clinical effects, HER2-targeted therapy remains in its infancy due to its resulting inherent and acquired resistance. Here, a comprehensive overview of HER2 in numerous cancers is presented, including its biological role, involved signaling pathways, and the status of HER2-targeted therapy.
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Affiliation(s)
- Xiao-Nan Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Xi-Ya Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ning-Jie Guo
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Wen-Qing Hou
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Shu-Wu Wang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ning Wang
- The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
| | - Bo Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
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13
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Cabello P, Torres-Ruiz S, Adam-Artigues A, Forés-Martos J, Martínez MT, Hernando C, Zazo S, Madoz-Gúrpide J, Rovira A, Burgués O, Rojo F, Albanell J, Lluch A, Bermejo B, Cejalvo JM, Eroles P. miR-146a-5p Promotes Angiogenesis and Confers Trastuzumab Resistance in HER2+ Breast Cancer. Cancers (Basel) 2023; 15:cancers15072138. [PMID: 37046799 PMCID: PMC10093389 DOI: 10.3390/cancers15072138] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/17/2023] [Accepted: 03/31/2023] [Indexed: 04/08/2023] Open
Abstract
Trastuzumab treatment has significantly improved the prognosis of HER2-positive breast cancer patients. Despite this, resistance to therapy still remains the main clinical challenge. In order to evaluate the implication of microRNAs in the trastuzumab response, we performed a microRNA array in parental and acquired trastuzumab-resistant HER2-positive breast cancer cell lines. Our results identified miR-146a-5p as the main dysregulated microRNA. Interestingly, high miR-146a-5p expression in primary tumor tissue significantly correlated with shorter disease-free survival in HER2-positive breast cancer patients. The gain- and loss-of-function of miR-146a-5p modulated the response to trastuzumab. Furthermore, the overexpression of miR-146a-5p increased migration and angiogenesis, and promoted cell cycle progression by reducing CDKN1A expression. Exosomes from trastuzumab-resistant cells showed a high level of miR-146a-5p expression compared with the parental cells. In addition, the co-culture with resistant cells’ exosomes was able to decrease in sensitivity and increase the migration capacities in trastuzumab-sensitive cells, as well as angiogenesis in HUVEC-2 cells. Collectively, these data support the role of miR-146a-5p in resistance to trastuzumab, and demonstrate that it can be transferred by exosomes conferring resistance properties to other cells.
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Affiliation(s)
- Paula Cabello
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- International University of Valencia—VIU, 46002 Valencia, Spain
| | | | | | | | - María Teresa Martínez
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Department of Medical Oncology, University Clinical Hospital of Valencia, 46010 Valencia, Spain
| | - Cristina Hernando
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Department of Medical Oncology, University Clinical Hospital of Valencia, 46010 Valencia, Spain
| | - Sandra Zazo
- Department of Pathology, Jiménez Díaz Foundation, 28040 Madrid, Spain
| | | | - Ana Rovira
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
- Department of Medical Oncology, Hospital del Mar, 08003 Barcelona, Spain
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
| | - Octavio Burgués
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
- Department of Pathology, University Clinical Hospital of Valencia, 46010 Valencia, Spain
| | - Federico Rojo
- Department of Pathology, Jiménez Díaz Foundation, 28040 Madrid, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
| | - Joan Albanell
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
- Department of Medical Oncology, Hospital del Mar, 08003 Barcelona, Spain
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
| | - Ana Lluch
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Department of Medical Oncology, University Clinical Hospital of Valencia, 46010 Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
- Department of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Begoña Bermejo
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Department of Medical Oncology, University Clinical Hospital of Valencia, 46010 Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
| | - Juan Miguel Cejalvo
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Department of Medical Oncology, University Clinical Hospital of Valencia, 46010 Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
| | - Pilar Eroles
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), 28040 Madrid, Spain
- Department of Physiology, University of Valencia, 46010 Valencia, Spain
- Department of Biotechnology, Polytechnic University of Valencia, 46022 Valencia, Spain
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14
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PIK3CA mutations are associated with pathologic complete response rate to neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer. Br J Cancer 2023; 128:121-129. [PMID: 36323880 PMCID: PMC9814131 DOI: 10.1038/s41416-022-02021-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 10/06/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Neoadjuvant treatment with a dual anti-human epidermal growth factor receptor 2 (HER2) blockade with pyrotinib and trastuzumab has been shown to be effective for HER2-positive breast cancer. METHODS The genomic characteristics of 425 cancer-related genes from the archived tumour blocks of 50 patients enrolled in a prospective neoadjuvant pyrotinib and trastuzumab plus chemotherapy clinical trial (ChiCTR1900022293) were assessed by next-generation sequencing (NGS). The relationship between tumour biomarkers and the postoperative pathological complete response (pCR) were explored. RESULTS Forty-five patients completed neoadjuvant chemotherapy and final surgery, of which 26 (58%) achieved a pCR. Among all driver gene mutations, PIK3CA mutation was screened out for having a significant relationship with the treatment response. The pCR rate of patients with wild-type PIK3CA was significantly higher than patients with mutated PIK3CA (80.8% vs. 26.3%; P = 0.00057), and remained significant after a multiple comparison adjustment (Padjusted = 0.024). We further evaluated the predictive value with logistic regression model of clinical features, genetic biomarkers or both, an AUC of 0.912 (95% CI: 0.827-0.997) was achieved in the integrated model. CONCLUSIONS Our data suggest that HER2-positive breast cancers with activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy.
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15
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Tumorigenicity of EGFR- and/or HER2-Positive Breast Cancers Is Mediated by Recruitment of Tumor-Associated Macrophages. Int J Mol Sci 2023; 24:ijms24021443. [PMID: 36674955 PMCID: PMC9866454 DOI: 10.3390/ijms24021443] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/27/2022] [Accepted: 01/09/2023] [Indexed: 01/13/2023] Open
Abstract
Basal-like breast cancer (BLBC) has a clinically aggressive nature. It is prevalent in young women and is known to often relapse rapidly. To date, the molecular mechanisms regarding the aggressiveness of BLBC have not been fully understood. In the present study, mechanisms of aggressiveness of BLBC involving EGFR and/or HER2 expression and interactions between tumor and tumor-associated macrophages (TAMs) were explored. The prognosis of breast cancer patients who underwent surgery at Samsung Medical Center was analyzed. It was found that the co-expression of EGFR and HER2 was associated with a worse prognosis. Therefore, we generated EGFR-positive BLBC cells with stable HER2 overexpression and analyzed the profile of secretory cytokines. Chemokine (C-C motif) ligand 2 (CCL2) expression was increased in HER2-overexpressed BLBC cells. Recombinant human CCL2 treatment augmented the motility of TAMs. In addition, the conditioned culture media of HER2-overexpressed BLBC cells increased the motility of TAMs. Furthermore, activation of TAMs by CCL2 or the conditioned culture media of HER2-overexpressed cells resulted in the production of pro-inflammatory cytokines, such as IL-8 and IL-1β. These observations reveal that CCL2 derived from EGFR and HER2 co-expressed BLBC cells can lead to increased TAM recruitment and the induction of IL-8 and IL-1β from recruited TAMs, triggering the tumorigenesis of breast cancer with the expression of both EGFR and HER2. Our findings demonstrate that EGFR+ and HER2+ BLBC aggressiveness is partially mediated through the interaction between BLBC and TAMs recruited by CCL2.
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16
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Shi Q, Xuhong J, Tian H, Qu M, Zhang Y, Jiang J, Qi X. Predictive and prognostic value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors: A systematic review and meta-analysis. Biochim Biophys Acta Rev Cancer 2023; 1878:188847. [PMID: 36516931 DOI: 10.1016/j.bbcan.2022.188847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/15/2022] [Accepted: 12/03/2022] [Indexed: 12/14/2022]
Abstract
This systematic review and meta-analysis study investigates the predictive and prognostic value of PIK3CA mutations for HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs). A search of the Medline, Embase, and Cochrane Library databases yielded 17 eligible studies (1706 patients). In 10 neoadjuvant studies, the pathological complete response rate was significantly higher in wild-type PIK3CA (WT) patients than in mutated PIK3CA (MT) patients (OR = 0.45; 95% CI = 0.31-0.65; P < 0.001). In five metastasis studies, the pooled objective response rate was significantly higher in WT patients than in MT patients (OR = 0.40; 95% CI = 0.23-0.70; P = 0.001). Four metastasis studies indicated that PIK3CA mutations had a marginally significant relationship with poor progression-free survival and overall survival. Thus, PIK3CA mutations have predictive value for the treatment response of early/advanced-stage HER2-positive breast cancer treated with TKI-containing regimens.
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Affiliation(s)
- Qiyun Shi
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China
| | - Juncheng Xuhong
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China
| | - Hao Tian
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China
| | - Man Qu
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China
| | - Yi Zhang
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China
| | - Jun Jiang
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China.
| | - Xiaowei Qi
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China.
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17
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Chow CY, Lie EF, Wu CH, Chow LW. Clinical implication of genetic composition and molecular mechanism on treatment strategies of HER2-positive breast cancers. Front Oncol 2022; 12:964824. [PMID: 36387174 PMCID: PMC9659858 DOI: 10.3389/fonc.2022.964824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/14/2022] [Indexed: 12/01/2022] Open
Abstract
The current clinical management model of HER2-positive breast cancers is commonly based on guidelines, which in turn are based on the design and outcome of clinical trials. While this model is useful to most practicing clinicians, the treatment outcome of individual patient is not certain at the start of treatment. As the understanding of the translational research of carcinogenesis and the related changes in cancer genetics and tumor microenvironment during treatment is critical in the selection of right choice of treatment to maximize the successful clinical outcome for the patient, this review article intends to discuss the latest developments in the genetic and molecular mechanisms of cancer progression and treatment resistance, and how they influence the planning of the treatment strategies of HER2-positive breast cancers.
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Affiliation(s)
- Christopher Y.C. Chow
- UNIMED Medical Institute, Hong Kong, Hong Kong SAR, China
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | | | - Cheng-Hsun Wu
- Department of Anatomy, China Medical University, Taichung, Taiwan
| | - Louis W.C. Chow
- UNIMED Medical Institute, Hong Kong, Hong Kong SAR, China
- Organisation for Oncology and Translational Research, Hong Kong, Hong Kong SAR, China
- *Correspondence: Louis W.C. Chow,
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18
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Adam-Artigues A, Arenas EJ, Martínez-Sabadell A, Brasó-Maristany F, Cervera R, Tormo E, Hernando C, Martínez MT, Carbonell-Asins J, Simón S, Poveda J, Moragón S, Zazo S, Martínez D, Rovira A, Burgués O, Rojo F, Albanell J, Bermejo B, Lluch A, Prat A, Arribas J, Eroles P, Cejalvo JM. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. SCIENCE ADVANCES 2022; 8:eabk2746. [PMID: 35594351 PMCID: PMC9122332 DOI: 10.1126/sciadv.abk2746] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 04/05/2022] [Indexed: 06/15/2023]
Abstract
Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer.
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Affiliation(s)
| | - Enrique J. Arenas
- Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
| | - Alex Martínez-Sabadell
- Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain
| | - Fara Brasó-Maristany
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona 08036, Spain
- Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona 08036, Spain
| | | | - Eduardo Tormo
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
| | - Cristina Hernando
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
| | - María Teresa Martínez
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
| | | | - Soraya Simón
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
| | - Jesús Poveda
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
| | - Santiago Moragón
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
| | - Sandra Zazo
- Department of Pathology, IIS Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Débora Martínez
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona 08036, Spain
- Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona 08036, Spain
| | - Ana Rovira
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Medical Oncology, Hospital del Mar, Barcelona 08003, Spain
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Spain
| | - Octavio Burgués
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Pathology, Hospital Clínico Universitario de València, Valencia 46010, Spain
| | - Federico Rojo
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Pathology, IIS Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Joan Albanell
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Medical Oncology, Hospital del Mar, Barcelona 08003, Spain
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Spain
- Pompeu Fabra University (UPF), Barcelona 08002, Spain
| | - Begoña Bermejo
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
| | - Ana Lluch
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
- Department of Medicine, Universidad de Valencia, Valencia 46010, Spain
| | - Aleix Prat
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona 08036, Spain
- Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona 08036, Spain
- SOLTI Breast Cancer Research Group, Barcelona 08008, Spain
| | - Joaquín Arribas
- Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Spain
- Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Barcelona 08193, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain
| | - Pilar Eroles
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Physiology, Universidad de Valencia, Valencia 46010, Spain
| | - Juan Miguel Cejalvo
- INCLIVA Biomedical Research Institute, Valencia 46010, Spain
- Center for Biomedical Network Research on Cancer (CIBERONC), Madrid 28019, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de València, Valencia 46010, Spain
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19
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LPIN1 Induces Gefitinib Resistance in EGFR Inhibitor-Resistant Non-Small Cell Lung Cancer Cells. Cancers (Basel) 2022; 14:cancers14092222. [PMID: 35565351 PMCID: PMC9102170 DOI: 10.3390/cancers14092222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/24/2022] [Accepted: 04/27/2022] [Indexed: 12/04/2022] Open
Abstract
Drug resistance limits the efficacy of targeted therapies, including tyrosine kinase inhibitors (TKIs); however, a substantial portion of the drug resistance mechanisms remains unexplained. In this study, we identified LPIN1 as a key factor that regulates gefitinib resistance in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) cells. Unlike TKI-sensitive HCC827 cells, gefitinib treatment induced LPIN1 expression and increased diacylglycerol concentration in TKI-resistant H1650 cells, followed by the activation of protein kinase C delta and nuclear factor kappa B (NF-κB) in an LPIN1-dependent manner, resulting in cancer cell survival. Additionally, LPIN1 increased the production of lipid droplets, which play an important role in TKI drug resistance. All results were recapitulated in a patient-derived EGFR-mutant NSCLC cell line. In in vivo tumorigenesis assay, we identified that both shRNA-mediated depletion and pharmaceutical inhibition of LPIN1 clearly reduced tumor growth and confirmed that gefitinib treatment induced LPIN1 expression and LPIN1-dependent NF-κB activation (an increase in p-IκBα level) in tumor tissues. These results suggest an effective strategy of co-treating TKIs and LPIN1 inhibitors to prevent TKI resistance in NSCLC patients.
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Chedid J, Allam S, Chamseddine N, Bou Zerdan M, El Nakib C, Assi HI. Role of circulating tumor DNA and circulating tumor cells in breast cancer: History and updates. SAGE Open Med 2022; 10:20503121221077838. [PMID: 35223029 PMCID: PMC8874178 DOI: 10.1177/20503121221077838] [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: 09/07/2021] [Accepted: 01/17/2022] [Indexed: 11/15/2022] Open
Abstract
Circulating tumor DNA, cell-free DNA, and circulating tumor cells have been at the epitome of recent research in breast cancer. These forms of liquid biopsies have been used in monitoring disease progression, estimating the risk of relapse, and response to treatment. Much has been done in relation to serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. Some studies have also explored their use in monitoring treatment response. As the field of liquid biopsies expands, more prospective studies are needed to tailor management in an individualistic approach. In this literature review, the authors explore the multiple uses of circulating tumor DNA and circulating tumor cells in breast cancer.
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Affiliation(s)
- Julien Chedid
- Department of Obstetrics and Gynecology, Saint George Hospital University Medical Center, Beirut, Lebanon
| | - Sabine Allam
- Faculty of Medicine, University of Balamand, Beirut, Lebanon
| | - Nathalie Chamseddine
- Department of Obstetrics and Gynecology, Saint George Hospital University Medical Center, Beirut, Lebanon
| | - Maroun Bou Zerdan
- Division of Hematology and Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
| | - Clara El Nakib
- Division of Hematology and Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
| | - Hazem I Assi
- Division of Hematology and Oncology, Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
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21
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Wynn CS, Tang SC. Anti-HER2 therapy in metastatic breast cancer: many choices and future directions. Cancer Metastasis Rev 2022; 41:193-209. [PMID: 35142964 PMCID: PMC8924093 DOI: 10.1007/s10555-022-10021-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/19/2022] [Indexed: 12/30/2022]
Abstract
Metastatic HER2 + breast cancer is an expanding area of drug development and research, with three new drugs approved in 2020 alone. While first-line therapy is well-established for metastatic HER2 + breast cancer, the standard of care for second-line therapy will likely be changing soon based on the results of the DESTINY-Breast03 trial. In the third-line setting, many options are available. Considerations in choosing between regimens in the third-line include resistance to trastuzumab, the presence of brain metastases, and tolerability. High rates of resistance exist in this setting particularly due to expression of p95, a truncated form of HER2 that constitutively activates downstream signaling pathways. We suggest a tyrosine kinase inhibitor (TKI)-based regimen because of the activity of TKIs in brain metastases and in p95-expressing tumors. Attempts to overcome resistance to anti-HER2 therapies with PI3K inhibitors, mTOR inhibitors, and CDK 4/6 inhibitors are an active area of research. In the future, biomarkers are needed to help predict which therapies patients may benefit from the most. We review the many new drugs in development, including those with novel mechanisms of action.
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Affiliation(s)
- Carrie S Wynn
- Cancer Center and Research Institute, University of Mississippi Medical Center, Guyton Research Building, G-651-07, 2500 North State Street, Jackson, MS, 39216, USA
| | - Shou-Ching Tang
- Cancer Center and Research Institute, University of Mississippi Medical Center, Guyton Research Building, G-651-07, 2500 North State Street, Jackson, MS, 39216, USA.
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22
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Mechanisms, Characteristics, and Treatment of Neuropathic Pain and Peripheral Neuropathy Associated with Dinutuximab in Neuroblastoma Patients. Int J Mol Sci 2021; 22:ijms222312648. [PMID: 34884452 PMCID: PMC8657961 DOI: 10.3390/ijms222312648] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/13/2021] [Accepted: 11/18/2021] [Indexed: 12/21/2022] Open
Abstract
Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed and resistant neuroblastoma patients. Five courses of dinutuximab 100 mg/m2 are usually administered as a 10-day continuous infusion or over 5 consecutive days every 5 weeks. Dinutuximab targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells and minimally present on the surface of normal human neurons, peripheral pain fibers, and skin melanocytes. Anti GD2 antibodies bind to surface GD2 and determine the lysis of neuroblastoma cells induced by immune response via the antibody-dependent cellular cytotoxicity and the complement-dependent cytotoxicity. Dinutuximab has significant side effects, including neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, photophobia, and hypotension. The most important side effect is neuropathic pain, which is triggered by the same antibody–antigen immune response, but generates ectopic activity in axons, which results in hyperalgesia and spontaneous pain. Pain can be severe especially in the first courses of dinutuximab infusion, and requires the administration of gabapentin and continuous morphine infusion. This paper will focus on the incidence, mechanisms, characteristics, and treatment of neuropathic pain and peripheral neuropathy due to dinutuximab administration in neuroblastoma patients.
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23
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Pareri AU, Koijam AS, Kumar C. Breaking the Silence of Tumor Response: Future Prospects of Targeted Radionuclide Therapy. Anticancer Agents Med Chem 2021; 22:1845-1858. [PMID: 34477531 DOI: 10.2174/1871520621666210903152354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/12/2021] [Accepted: 07/19/2021] [Indexed: 01/10/2023]
Abstract
Therapy-induced tumor resistance has always been a paramount hurdle in the clinical triumph of cancer therapy. Resistance acquired by tumor through interventions of chemotherapeutic drugs, ionizing radiation, and immunotherapy in the patientsis a severe drawback and major cause of recurrence of tumor and failure of therapeutic responses. To counter acquired resistance in tumor cells, several strategies are practiced such as chemotherapy regimens, immunotherapy, and immunoconjugates, but the outcome is very disappointing for the patients as well as clinicians. Radionuclide therapy using alpha or beta-emitting radionuclide as payload became state-of-the-art for cancer therapy. With the improvement in dosimetric studies, development of high-affinity target molecules, and design of several novel chelating agents which provide thermodynamically stable complexes in vivo, the scope of radionuclide therapy has increased by leaps and bounds. Additionally, radionuclide therapy along with the combination of chemotherapy is gaining importance in pre-clinics, which is quite encouraging. Thus, it opens an avenue for newer cancer therapy modalities where chemotherapy, radiation therapy, and immunotherapy are unable to break the silence of tumor response. This article describes, in brief, the causes of tumor resistance and discusses the potential of radionuclide therapy to enhance tumor response.
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Affiliation(s)
| | | | - Chandan Kumar
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre Mumbai-400085, India
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24
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Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels. Proc Natl Acad Sci U S A 2021; 118:2023868118. [PMID: 34266948 PMCID: PMC8307381 DOI: 10.1073/pnas.2023868118] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
A significant pool of HER2+ breast cancer patients are either unresponsive or become resistant to standards of care. New therapeutic approaches exploiting the tumor microenvironment, including immunotherapies, are attractive. Hypoxia shapes the tumor microenvironment toward therapy resistance and metastasis. Here, we report a role for AXL receptor tyrosine kinase in the hypoxic response by promoting HIF-1α expression. Interfering with Axl in a preclinical model of HER2+ breast cancer normalizes the blood vessels and promotes a proinflammatory microenvironment that enhances immunotherapy response to reduce the primary and metastatic tumor burdens. Clinical trials so far suggest that achieving immunotherapy responses in HER2+ cancers might be challenging, and our data might provide an important insight to circumvent a roadblock. Hypoxia is an important phenomenon in solid tumors that contributes to metastasis, tumor microenvironment (TME) deregulation, and resistance to therapies. The receptor tyrosine kinase AXL is an HIF target, but its roles during hypoxic stress leading to the TME deregulation are not well defined. We report here that the mammary gland–specific deletion of Axl in a HER2+ mouse model of breast cancer leads to a normalization of the blood vessels, a proinflammatory TME, and a reduction of lung metastases by dampening the hypoxic response in tumor cells. During hypoxia, interfering with AXL reduces HIF-1α levels altering the hypoxic response leading to a reduction of hypoxia-induced epithelial-to-mesenchymal transition (EMT), invasion, and production of key cytokines for macrophages behaviors. These observations suggest that inhibition of Axl generates a suitable setting to increase immunotherapy. Accordingly, combining pharmacological inhibition of Axl with anti–PD-1 in a preclinical model of HER2+ breast cancer reduces the primary tumor and metastatic burdens, suggesting a potential therapeutic approach to manage HER2+ patients whose tumors present high hypoxic features.
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25
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Shiravi F, Mohammadi M, Golsaz-Shirazi F, Bahadori T, Judaki MA, Fatemi F, Zare HA, Haghighat FN, Mobini M, Jeddi-Tehrani M, Amiri MM, Shokri F. Potent synergistic anti-tumor activity of a novel humanized anti-HER2 antibody hersintuzumab in combination with trastuzumab in xenograft models. Invest New Drugs 2021; 39:697-704. [PMID: 33389387 DOI: 10.1007/s10637-020-01048-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/09/2020] [Indexed: 11/28/2022]
Abstract
Immunotherapy of HER2-overexpressing cancers by FDA approved monoclonal antibodies (mAbs) such as trastuzumab and pertuzumab has shown promising results. We have recently produced a novel humanized anti-HER2 mAb, hersintuzumab, which did not sterically inhibit binding of trastuzumab and pertuzumab to HER2, thus recognizing a distinct epitope on subdomain I + II of HER2. In this study, we assessed the in vitro and in vivo anti-tumor activity of this mAb individually and in combination with trastuzumab. Different HER2-overexpressing human cancer cell lines, including SKOV3, NCI-N87 HCC1954 and BT-474 were cultured and binding reactivity of Hersintuzumab to these cell lines was analyzed by flow cytometry. In addition, the inhibitory effect of different concentrations of hersintuzumab, trastuzumab and their combination on tumor cells growth was assessed by XTT assay. For Assessment of tumor growth inhibition in xenograft model, Balb/c athymic nude mice were subcutaneously injected with NCI-N87 and SKOV3 tumor cells and then treated intravenously with these mAbs. Our results showed that hersintuzumab could bind to all HER2-overexpressing cell lines similar to trastuzumab. In vitro experiments showed that both hersintuzumab and trastuzumab individually and in combination inhibited growth of all cell lines with the exception of HCC-1954.Inhibitory effect of the combination of mAbs was significantly higher than that of each mAb alone. Similar results were obtained in the gastric (NCI-N87) and ovarian (SKOV-3) tumor xenograft models. Hersintuzumab in combination with trastuzumab induces synergic anti-tumor effects on HER2-overexpressing cells in vitro and in vivo and is potentially a therapeutic tool for treatment of HER2-overexpressing cancers.
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Affiliation(s)
- Fariba Shiravi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mohammadi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Tannaz Bahadori
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Judaki
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Forough Fatemi
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Hengameh Ahmadi Zare
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | | | - Maryam Mobini
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmood Jeddi-Tehrani
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Mohammad Mehdi Amiri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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26
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Gao C, Li H, Liu C, Xu X, Zhuang J, Zhou C, Liu L, Feng F, Sun C. Tumor Mutation Burden and Immune Invasion Characteristics in Triple Negative Breast Cancer: Genome High-Throughput Data Analysis. Front Immunol 2021; 12:650491. [PMID: 33968045 PMCID: PMC8097167 DOI: 10.3389/fimmu.2021.650491] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
In recent years, the emergence of immunotherapy has provided a new perspective for the treatment and management of triple-negative breast cancer (TNBC). However, the relationship between tumor mutation burden (TMB) and immune infiltration and the prognosis of TNBC remains unclear. In this study, to explore the immunogenicity of TNBC, we divided patients with TNBC into high and low TMB groups based on the somatic mutation data of TNBC in The Cancer Genome Atlas (TCGA), and screened out genes with mutation rate ≥10. Then, Kaplan-Meier survival analysis revealed that the 5-year survival rate of the high TMB group was much higher than that of the low TMB group and the two groups also showed differences in immune cell infiltration. Further exploration found that the FAT3 gene, which displays significant difference and a higher mutation rate between the two groups, is not only significantly related to the prognosis of TNBC patients but also exhibits difference in immune cell infiltration between the wild group and the mutant group of the FAT3 gene. The results of gene set enrichment analysis and drug sensitivity analysis further support the importance of the FAT3 gene in TNBC. This study reveals the characteristics of TMB and immune cell infiltration in triple-negative breast cancer and their relationship with prognosis, to provide new biomarkers and potential treatment options for the future treatment of TNBC. The FAT3 gene, as a risk predictor gene of TNBC, is considered a potential biological target and may provide new insight for the treatment of TNBC.
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Affiliation(s)
- Chundi Gao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Huayao Li
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Cun Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaowei Xu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jing Zhuang
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China
| | - Chao Zhou
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lijuan Liu
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fubin Feng
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Changgang Sun
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China.,Qingdao Academy of Chinese Medical Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, China
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27
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Application of Tucatinib and Trastuzumab: Dual Anti HER2 Therapy Against HER2 Positive Breast Cancer. Indian J Clin Biochem 2021; 36:124-125. [PMID: 33505137 DOI: 10.1007/s12291-019-00863-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 11/25/2019] [Indexed: 10/25/2022]
Abstract
Synergism in action of tucatinib and trastumab is reported in breast cancer management. However, its molecular basis is yet to be determined. In this context we attempted to provide an explanation at the molecular level by performing in silico experimentation and coupling its result with already available published observations. Our study will provide basis for planning further experimental study for unravelling the truth.
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28
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Ghosh M, Naik R, Lingaraju SM, Susheela SP, Patil S, Srinivasachar GK, Thungappa SC, Murugan K, Jayappa SB, Bhattacharjee S, Rao N, Bandimegal M, Krishnappa R, Poppareddy SH, Raghavendrachar KC, Shivakumar Y, Nagesh S, Kodandapani R, Rajan A, Bahadur U, Agrawal P, Ramaswamy V, Nanjaiah TB, Kunigal S, Katragadda S, Manjunath A, Ram A, Ajaikumar BS. Landscape of clinically actionable mutations in breast cancer 'A cohort study'. Transl Oncol 2021; 14:100877. [PMID: 33099186 PMCID: PMC7581976 DOI: 10.1016/j.tranon.2020.100877] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 08/31/2020] [Accepted: 09/01/2020] [Indexed: 01/16/2023] Open
Abstract
Breast cancer (BC) is a heterogeneous disease. Numerous chemotherapeutic agents are available for early stage or advanced/metastatic breast cancer to provide maximum benefit with minimum side effects. However, the clinical outcome of patients with the same clinical and pathological characteristics and treated with similar treatments may show major differences and a vast majority of patients still develop treatment resistance and eventually succumb to disease. It remains an unmet need to identify specific molecular defects, new biomarkers to enable clinicians to adopt individualized treatment for every patient in terms of endocrine, chemotherapy or targeted therapy which will improve clinical outcomes in BC. Our study aimed to identify frequent hotspot mutation profile in BC by targeted deep sequencing in cancer-related genes using Illumina Truseq amplicon/Swift Accel-Amplicon panel and MiSeq technology in an IRB-approved prospective study in a CLIA compliant laboratory. All the cases had pathology review for stage, histological type, hormonal status and Ki-67. Data was processed using Strand NGS™. Mutations identified in the tumor were assessed for 'actionability' i.e. response to therapy and impact on prognosis.
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Affiliation(s)
| | - Radheshyam Naik
- HealthCare Global Enterprises Limited, Bangalore, Karnataka 560027, India
| | | | | | - Shekar Patil
- HealthCare Global Enterprises Limited, Bangalore, Karnataka 560027, India
| | | | | | - Krithika Murugan
- HealthCare Global Enterprises Limited, Bangalore, Karnataka 560027, India
| | | | | | - Nalini Rao
- HealthCare Global Enterprises Limited, Bangalore, Karnataka 560027, India
| | - Mahesh Bandimegal
- HealthCare Global Enterprises Limited, Bangalore, Karnataka 560027, India
| | - Roopesh Krishnappa
- HealthCare Global Enterprises Limited, Bangalore, Karnataka 560027, India
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Amritanshu Ram
- HealthCare Global Enterprises Limited, Bangalore, Karnataka 560027, India
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29
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Mitani S, Kawakami H. Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance. Cancers (Basel) 2020; 12:E400. [PMID: 32050652 PMCID: PMC7072407 DOI: 10.3390/cancers12020400] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/25/2020] [Accepted: 02/06/2020] [Indexed: 12/15/2022] Open
Abstract
Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies.
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Affiliation(s)
| | - Hisato Kawakami
- Department of Medical Oncology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan;
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30
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Fernández-Nogueira P, Mancino M, Fuster G, López-Plana A, Jauregui P, Almendro V, Enreig E, Menéndez S, Rojo F, Noguera-Castells A, Bill A, Gaither LA, Serrano L, Recalde-Percaz L, Moragas N, Alonso R, Ametller E, Rovira A, Lluch A, Albanell J, Gascon P, Bragado P. Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation. Clin Cancer Res 2019; 26:1432-1448. [DOI: 10.1158/1078-0432.ccr-19-0353] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 09/15/2019] [Accepted: 11/04/2019] [Indexed: 11/16/2022]
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31
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Lim SB, Lim CT, Lim WT. Single-Cell Analysis of Circulating Tumor Cells: Why Heterogeneity Matters. Cancers (Basel) 2019; 11:cancers11101595. [PMID: 31635038 PMCID: PMC6826423 DOI: 10.3390/cancers11101595] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/15/2019] [Accepted: 10/16/2019] [Indexed: 12/31/2022] Open
Abstract
Unlike bulk-cell analysis, single-cell approaches have the advantage of assessing cellular heterogeneity that governs key aspects of tumor biology. Yet, their applications to circulating tumor cells (CTCs) are relatively limited, due mainly to the technical challenges resulting from extreme rarity of CTCs. Nevertheless, recent advances in microfluidics and immunoaffinity enrichment technologies along with sequencing platforms have fueled studies aiming to enrich, isolate, and sequence whole genomes of CTCs with high fidelity across various malignancies. Here, we review recent single-cell CTC (scCTC) sequencing efforts, and the integrated workflows, that have successfully characterized patient-derived CTCs. We examine how these studies uncover DNA alterations occurring at multiple molecular levels ranging from point mutations to chromosomal rearrangements from a single CTC, and discuss their cellular heterogeneity and clinical consequences. Finally, we highlight emerging strategies to address key challenges currently limiting the translation of these findings to clinical practice.
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Affiliation(s)
- Su Bin Lim
- NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore 117456, Singapore.
- Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore.
| | - Chwee Teck Lim
- NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore 117456, Singapore.
- Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore.
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore.
- Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore 117599, Singapore.
| | - Wan-Teck Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
- Office of Academic and Clinical Development, Duke-NUS Medical School, Singapore 169857, Singapore.
- IMCB NCC MPI Singapore Oncogenome Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore.
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32
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Keyel ME, Reynolds CP. Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. Biologics 2018; 13:1-12. [PMID: 30613134 PMCID: PMC6306059 DOI: 10.2147/btt.s114530] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Neuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system which accounts for 8% of childhood cancers. Most NBs express high levels of the disialoganglioside GD2. Several antibodies have been developed to target GD2 on NB, including the human/mouse chimeric antibody ch14.18, known as dinutuximab. Dinutuximab used in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin (13-cis-retinoic acid) has a US Food and Drug Administration (FDA)-registered indication for treating high-risk NB patients who achieved at least a partial response to prior first-line multi-agent, multimodality therapy. The FDA registration resulted from a prospective randomized trial assessing the benefit of adding dinutuximab + cytokines to post-myeloablative maintenance therapy for high-risk NB. Dinutuximab has also shown promising antitumor activity when combined with temozolomide and irinotecan in treating NB progressive disease. Clinical activity of dinutuximab and other GD2-targeted therapies relies on the presence of the GD2 antigen on NB cells. Some NBs have been reported as GD2 low or negative, and such tumor cells could be nonresponsive to anti-GD2 therapy. As dinutuximab relies on complement and effector cells to mediate NB killing, factors affecting those components of patient response may also decrease dinutuximab effectiveness. This review summarizes the development of GD2 antibody-targeted therapy, the use of dinutuximab in both up-front and salvage therapy for high-risk NB, and the potential mechanisms of resistance to dinutuximab.
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Affiliation(s)
| | - C Patrick Reynolds
- Cancer Center,
- Department of Pediatrics,
- Department of Internal Medicine,
- Department of Cell Biology & Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA,
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33
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Chemotherapeutic resistance: a nano-mechanical point of view. Biol Chem 2018; 399:1433-1446. [DOI: 10.1515/hsz-2018-0274] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 07/19/2018] [Indexed: 12/17/2022]
Abstract
AbstractChemotherapeutic resistance is one of the main obstacles for cancer remission. To understand how cancer cells acquire chemotherapeutic resistance, biochemical studies focusing on drug target alteration, altered cell proliferation, and reduced susceptibility to apoptosis were performed. Advances in nano-mechanobiology showed that the enhanced mechanical deformability of cancer cells accompanied by cytoskeletal alteration is a decisive factor for cancer development. Furthermore, atomic force microscopy (AFM)–based nano-mechanical studies showed that chemotherapeutic treatments reinforced the mechanical stiffness of drug-sensitive cancer cells. However, drug-resistant cancer cells did not show such mechanical responses following chemotherapeutic treatments. Interestingly, drug-resistant cancer cells are mechanically heterogeneous, with a subpopulation of resistant cells showing higher stiffness than their drug-sensitive counterparts. The signaling pathways involving Rho, vinculin, and myosin II were found to be responsible for these mechanical alterations in drug-resistant cancer cells. In the present review, we highlight the mechanical aspects of chemotherapeutic resistance, and suggest how mechanical studies can contribute to unravelling the multifaceted nature of chemotherapeutic resistance.
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34
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Park YH, Lee KH, Sohn JH, Lee KS, Jung KH, Kim JH, Lee KH, Ahn JS, Kim TY, Kim GM, Park IH, Kim SB, Kim SH, Han HS, Im YH, Ahn JH, Kim JY, Kang J, Im SA. A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial. Int J Cancer 2018; 143:3240-3247. [DOI: 10.1002/ijc.31651] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 03/22/2018] [Accepted: 04/10/2018] [Indexed: 01/27/2023]
Affiliation(s)
- Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul South Korea
| | - Kyung-Hun Lee
- Department of Internal Medicine; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine; Seoul South Korea
| | - Joo Hyuk Sohn
- Department of Internal Medicine, Yonsei Cancer Center; Seoul South Korea
| | - Keun Seok Lee
- Center for Breast Cancer, National Cancer Center Hospital; Goyang South Korea
| | - Kyung Hae Jung
- Department of Oncology, Asan Medical Center; University of Ulsan College of Medicine; Seoul South Korea
| | - Jee-Hyun Kim
- Department of Internal Medicine; Seoul National University Bundang Hospital, Seoul National University College of Medicine; Soengnam South Korea
| | - Ki Hyeong Lee
- Department of Internal Medicine; Chungbuk National University Hospital; Cheongju South Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul South Korea
| | - Tae-Yong Kim
- Department of Internal Medicine; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine; Seoul South Korea
| | - Gun Min Kim
- Department of Internal Medicine, Yonsei Cancer Center; Seoul South Korea
| | - In Hae Park
- Center for Breast Cancer, National Cancer Center Hospital; Goyang South Korea
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center; University of Ulsan College of Medicine; Seoul South Korea
| | - Se Hyun Kim
- Department of Internal Medicine; Seoul National University Bundang Hospital, Seoul National University College of Medicine; Soengnam South Korea
| | - Hye Sook Han
- Department of Internal Medicine; Chungbuk National University Hospital; Cheongju South Korea
| | - Young-Hyuck Im
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul South Korea
| | - Jin-Hee Ahn
- Department of Oncology, Asan Medical Center; University of Ulsan College of Medicine; Seoul South Korea
| | - Jung-Yong Kim
- Clinical Development Division; National OncoVenture; Goyang South Korea
| | - Jahoon Kang
- Clinical Research and Development; Hanmi Pharmaceutical Co., Ltd.; Seoul South Korea
| | - Seock-Ah Im
- Department of Internal Medicine; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine; Seoul South Korea
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Adamczyk A, Kruczak A, Harazin-Lechowska A, Ambicka A, Grela-Wojewoda A, Domagała-Haduch M, Janecka-Widła A, Majchrzyk K, Cichocka A, Ryś J, Niemiec J. Relationship between HER2 gene status and selected potential biological features related to trastuzumab resistance and its influence on survival of breast cancer patients undergoing trastuzumab adjuvant treatment. Onco Targets Ther 2018; 11:4525-4535. [PMID: 30122944 DOI: 10.2147/ott.s166983] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Background The aim of the study was to investigate if parameters associated with human epidermal growth factor receptor type 2 (HER2) status (HER2 gene copy number, HER2/CEP17 ratio or polysomy of chromosome 17) are related to various biological features potentially responsible for trastuzumab resistance (PTEN, IGF-1R, MUC4, EGFR, HER3, HER4, and mutation status of PIK3CA) as well as their influence on survival of HER2-positive breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Patients and methods The investigated group consisted of 117 patients with invasive ductal breast cancer (T≥1, N≥0, M0) with overexpression of HER2, who underwent radical surgery between 2007 and 2014. Status of ER, PR, and HER2 expression was retrieved from patients' files. HER2 gene copy number was investigated by fluorescence in situ hybridization using PathVysion HER-2 DNA Probe Kit II. Expression of PTEN, IGF-1R, MUC4, EGFR, HER3, and HER4 was assessed immunohistochemically on formalin-fixed paraffin-embedded tissue sections. PIK3C mutation status was determined by qPCR analysis. Results Overexpression of HER2 protein (IHC 3+) and ER negativity corresponded to higher HER22 copy number and HER2/CEP17 ratio (.<0.001). Tumors with polysomy were characterized by higher HER22 gene copy number but lower HER2/CEP17p ratio (p<0.026, p<0.001). Patients with tumors featuring HER3 immunonegativity or low HER2/CEP17 ratio (#4) were characterized by 100% metastasis-free survival (.=0.018, p=0.062). Conclusion Presence of both unfavorable factors, ie, HER3 expression and high HER2/CEP17 ratio, allowed to distinguish a group of patients with worse prognosis (.=0.001).
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Affiliation(s)
| | | | | | | | - Aleksandra Grela-Wojewoda
- Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Małgorzata Domagała-Haduch
- Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
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Park S. Mechanical Alteration Associated With Chemotherapeutic Resistance of Breast Cancer Cells. J Cancer Prev 2018; 23:87-92. [PMID: 30003069 PMCID: PMC6037207 DOI: 10.15430/jcp.2018.23.2.87] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 06/20/2018] [Accepted: 06/20/2018] [Indexed: 11/07/2022] Open
Abstract
Background The mechanical deformability of cancer cells has attracted particular attention as an emerging biomarker for the prediction of anti-cancer drug sensitivity. Nevertheless, it has not been possible to establish a general rubric for the identification of drug susceptibility in breast cancer cells from a mechanical perspective. In the present study, we investigated the mechanical alteration associated with resistance to adjuvant therapy in breast cancer cells. Methods We performed an ‘atomic force microscopy (AFM)-based nanomechanical study’ on ‘drug-sensitive (MCF-7)’ and ‘drug-resistant (MCF-7/ADR)’ breast cancer cells. We also conducted cell viability tests to evaluate the difference in doxorubicin responsiveness between two breast cancer cell lines. We carried out a wound closure experiment to investigate the motility changes associated with chemotherapeutic resistance. To elucidate the changes in molecular alteration that accompany chemotherapeutic resistance, we investigated the expression of vinculin and integrin-linked kinase-1–which are proteins involved in substrate adhesion and the actin cytoskeleton–using Western blotting analysis. Results A MTT assay confirmed that the dose-dependent efficacy of doxorubicin was reduced in MCF-7/ADR cells compared to that in MCF-7 cells. The wound assay revealed enhanced two-dimensional motility in the MCF-7/ADR cells. The AFM mechanical assay showed evidence that the drug-resistant breast cancer cells exhibited a significant decrease in mechanical deformability compared to their drug-sensitive counterparts. The mechanical alteration in the MCF-7/ADR cells was accompanied by upregulated vinculin expression. Conclusions The obtained results manifestly showed that the altered mechanical signatures–including mechanical deformability and motility–were closely related with drug resistance in the breast cancer cells. We believe that this investigation has improved our understanding of the chemotherapeutic susceptibility of breast cancer cells.
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Affiliation(s)
- Soyeun Park
- College of Pharmacy, Keimyung University, Daegu, Korea
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37
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Almurshedi AS, Radwan M, Omar S, Alaiya AA, Badran MM, Elsaghire H, Saleem IY, Hutcheon GA. A novel pH-sensitive liposome to trigger delivery of afatinib to cancer cells: Impact on lung cancer therapy. J Mol Liq 2018. [DOI: 10.1016/j.molliq.2018.03.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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38
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Goyette MA, Duhamel S, Aubert L, Pelletier A, Savage P, Thibault MP, Johnson RM, Carmeliet P, Basik M, Gaboury L, Muller WJ, Park M, Roux PP, Gratton JP, Côté JF. The Receptor Tyrosine Kinase AXL Is Required at Multiple Steps of the Metastatic Cascade during HER2-Positive Breast Cancer Progression. Cell Rep 2018; 23:1476-1490. [PMID: 29719259 DOI: 10.1016/j.celrep.2018.04.019] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 02/21/2018] [Accepted: 04/03/2018] [Indexed: 12/14/2022] Open
Abstract
AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. In the current study, we report AXL expression in HER2-positive (HER2+) breast cancers where it correlates with poor patient survival. Using murine models of HER2+ breast cancer, Axl, but not its ligand Gas6, was found to be essential for metastasis. We determined that AXL is required for intravasation, extravasation, and growth at the metastatic site. We found that AXL is expressed in HER2+ cancers displaying epithelial-to-mesenchymal transition (EMT) signatures where it contributes to sustain EMT. Interfering with AXL in a patient-derived xenograft (PDX) impaired transforming growth factor β (TGF-β)-induced cell invasion. Last, pharmacological inhibition of AXL specifically decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential anti-metastatic co-therapeutic target for the treatment of HER2+ breast cancers.
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Affiliation(s)
- Marie-Anne Goyette
- Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada; Molecular Biology Programs, Université de Montréal, Montréal, QC H3T 1J4, Canada
| | - Stéphanie Duhamel
- Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada
| | - Léo Aubert
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Ariane Pelletier
- Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada
| | - Paul Savage
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A1, Canada
| | | | - Radia Marie Johnson
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A1, Canada
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Leuven 3000, Belgium
| | - Mark Basik
- Department of Oncology and Surgery, Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada
| | - Louis Gaboury
- Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - William J Muller
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A1, Canada
| | - Morag Park
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A1, Canada
| | - Philippe P Roux
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3C 3J7, Canada; Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Jean-Philippe Gratton
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Jean-François Côté
- Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada; Molecular Biology Programs, Université de Montréal, Montréal, QC H3T 1J4, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada.
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Shi K, Fang Y, Gao S, Yang D, Bi H, Xue J, Lu A, Li Y, Ke L, Lin X, Jin X, Li M. Inorganic kernel - Supported asymmetric hybrid vesicles for targeting delivery of STAT3-decoy oligonucleotides to overcome anti-HER2 therapeutic resistance of BT474R. J Control Release 2018; 279:53-68. [PMID: 29655990 DOI: 10.1016/j.jconrel.2018.04.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Revised: 04/07/2018] [Accepted: 04/11/2018] [Indexed: 12/18/2022]
Abstract
As a recombinant humanized monoclonal antibody that targets the extracellular region of HER2 tyrosine kinase receptor, trastuzumab (TRAZ) has demonstrated comparable clinical efficacy and improved survival in patients with HER2-positive breast cancer. Nevertheless, the therapeutic potential of TRAZ is often limited due to its frequent resistance to anti-HER2 therapy. Therefore, we investigate the reversal effect of STAT3-specific decoy oligonucleotides (STAT3-decoy ODNs) on TRAZ resistance, which contain the consensus sequence within the targeted gene promoter of STAT3. Considering the shortcomings of poor cellular permeability and rapid degradation in vivo limit the further clinical applications of ODNs, we report here an asymmetric hybrid lipid/polymer vesicles with calcium phosphate as the solid kernel (CaP@HA). Through hyaluronan-mediated CD44 targeting, the constructed vesicles can specifically carry STAT3-decoy ODNs into TRAZ-resistant breast cancer cells and then regulate TRAZ-induced apoptosis. In comparison with the native ones, ODNs packaged with CaP@HA showed significantly increased serum stability, cellular transfection, synergistic cytotoxicity and apoptosis in vitro. The improved TRAZ sensitization is attributed to the blockade of STAT3 signaling as well as the expression of downstream target genes associated with TRAZ resistance. With the synergistic action of STAT3-decoy ODNs loaded CaP@HA, TRAZ inhibited the growth of its resistant breast cancer xenograft dramatically and induced significant tumor cell apoptosis in vivo. These results suggested that CaP@HA mediated targeted delivery of STAT3-decoy ODNs might be a promising new strategy to overcome anti-HER2 resistance in breast cancer therapy.
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Affiliation(s)
- Kai Shi
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China.
| | - Yan Fang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Shan Gao
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Dongjuan Yang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Hongshu Bi
- Liaoning Yaolian Pharmaceutical Co., Ltd., Benxi, Liaoning 117004, PR China
| | - Jianxiu Xue
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Anqi Lu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Yuai Li
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Liyuan Ke
- Liaoning Cancer Hospital & Institue, Shenyang, Liaoning 110042, PR China
| | - Xiaojie Lin
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Xuechao Jin
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
| | - Min Li
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, PR China
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Kumar M, Sahu RK, Goyal A, Sharma S, Kaur N, Mehrotra R, Singh UR, Hedau S. BRCA1 Promoter Methylation and Expression - Associations with ER+, PR+ and HER2+ Subtypes of Breast Carcinoma. Asian Pac J Cancer Prev 2017; 18:3293-3299. [PMID: 29286222 PMCID: PMC5980886 DOI: 10.22034/apjcp.2017.18.12.3293] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Introduction: Considering the increasing trend in incidence rates, morbidity and mortality of breast cancer, there is
an urgent need to identify and validate new biomarkers for early detection and better management. The purpose of the
study was to investigate BRCA1 protein expression and promoter methylation of the BRCA1 gene and their association
with molecular subtypes based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth
factor receptor 2 (HER2) positivity. Materials and Methods: A total of 114 breast cancer tissue biopsies were collected
for methylation specific PCR (MSP) and immunohistochemical (IHC) analysis. Results: Seven tissue microarrays were
constructed. BRCA1 protein expression was reduced in 55/114 (48.2%) and in the majority of ER-negative tumors
(73.3%) (p<0.001). Similarly BRCA1 expression was reduced in the majority of PR-negative tumors (69.2%) but
without statistical significance (p value=0.083). BRCA1 methylation was positive in 59.6% cases. A subset regarding
ER+, PR+ and HER2+ was identified which consisted of 31.6% in which an inverse relationship between BRCA1
methylation and protein expression was noted. Conclusion: Reduced expression was associated with ER and PR
negative status which is linked with a poor prognosis. BRCA1 protein expression might thus be used as a prognostic
indicator to predict treatment response to hormone therapy.
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Affiliation(s)
- Mohit Kumar
- Department of Pathology, University Of Delhi, Delhi, India.
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Kwon S, Chin K, Nederlof M, Gray JW. Quantitative, in situ analysis of mRNAs and proteins with subcellular resolution. Sci Rep 2017; 7:16459. [PMID: 29184166 PMCID: PMC5705767 DOI: 10.1038/s41598-017-16492-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 11/13/2017] [Indexed: 12/27/2022] Open
Abstract
We describe here a method, termed immunoFISH, for simultaneous in situ analysis of the composition and distribution of proteins and individual RNA transcripts in single cells. Individual RNA molecules are labeled by hybridization and target proteins are concurrently stained using immunofluorescence. Multicolor fluorescence images are acquired and analyzed to determine the abundance, composition, and distribution of hybridized probes and immunofluorescence. We assessed the ability of immunoFISH to simultaneous quantify protein and transcript levels and distribution in cultured HER2 positive breast cancer cells and human breast tumor samples. We demonstrated the utility of this assay in several applications including demonstration of the existence of a layer of normal myoepithelial KRT14 expressing cells that separate HER2+ cancer cells from the stromal and immune microenvironment in HER2+ invasive breast cancer. Our studies show that immunoFISH provides quantitative information about the spatial heterogeneity in transcriptional and proteomic features that exist between and within cells.
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Affiliation(s)
- Sunjong Kwon
- Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, 2730 SW Moody Ave, Portland, OR, 97201, USA
| | - Koei Chin
- Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, 2730 SW Moody Ave, Portland, OR, 97201, USA
| | - Michel Nederlof
- Quantitative Imaging Systems, Inc., 1502 Fox Chapel Road, Pittsburgh, PA 15238, USA
| | - Joe W Gray
- Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, 2730 SW Moody Ave, Portland, OR, 97201, USA.
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Li Y, Wu S, Bai F. Molecular characterization of circulating tumor cells-from bench to bedside. Semin Cell Dev Biol 2017; 75:88-97. [PMID: 28899718 DOI: 10.1016/j.semcdb.2017.09.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 09/05/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023]
Abstract
Circulating tumor cells (CTCs) are cancer cells discovered in cancer patients' peripheral blood that successfully escape from the primary tumor site and/or metastases, struggle to survive in the bloodstream, and have potential for seeding metastases. Numerous methods have been proposed to capture CTCs. The value of CTCs as a means of understanding cancer metastasis and a major form of 'liquid biopsy' has been widely demonstrated. Recently, single-cell molecular analyses of CTCs have provided profound biological insights into tumor heterogeneity, mechanism of metastasis and tumor evolution. In addition, because CTC analysis is non-invasive, CTCs exhibit great potential as biomarkers for assessment of cancer prognosis and therapy response. In this review, we summarize modern technologies for CTC detection and isolation, single-cell genomic/transcriptomic characterization of CTCs, and prospective clinical applications of CTCs. We expect that, after further technical improvements in methods of detection and sequencing, CTC analyses will shed new light on the mechanisms driving cancer metastasis and benefit many cancer patients.
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Affiliation(s)
- Yanmeng Li
- Biodynamic Optical Imaging Center (BIOPIC), School of Life Science, Peking University, Beijing 100871, China
| | - Shaohan Wu
- Biodynamic Optical Imaging Center (BIOPIC), School of Life Science, Peking University, Beijing 100871, China
| | - Fan Bai
- Biodynamic Optical Imaging Center (BIOPIC), School of Life Science, Peking University, Beijing 100871, China.
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HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma. Breast Cancer Res Treat 2017; 166:447-457. [DOI: 10.1007/s10549-017-4453-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/07/2017] [Indexed: 12/01/2022]
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Zeng X, Che X, Liu YP, Qu XJ, Xu L, Zhao CY, Zheng CL, Hou KZ, Teng Y. FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells. Exp Ther Med 2017; 14:3265-3272. [PMID: 28912877 DOI: 10.3892/etm.2017.4873] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 04/28/2017] [Indexed: 12/18/2022] Open
Abstract
Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor α (ERα), and upregulated ERα-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERα were decreased, and trastuzumab-induced ERα target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERα-target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer.
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Affiliation(s)
- Xue Zeng
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yun-Peng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiu-Juan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Lu Xu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Chen-Yang Zhao
- Central Laboratory, The Fourth Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Chun-Lei Zheng
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Ke-Zuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yuee Teng
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Broughton MN, Westgaard A, Paus E, Øijordsbakken M, Henanger KJ, Naume B, Bjøro T. Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4). Tumour Biol 2017; 39:1010428317707436. [PMID: 28653892 DOI: 10.1177/1010428317707436] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The use of trastuzumab in patients with breast cancer that overexpresses human epidermal growth factor receptor 2 has significantly improved treatment outcomes. However, a substantial proportion of this patient group still experiences progression of the disease after receiving the drug. Evaluation of the changes in expression of the human epidermal growth factor receptors could be of interest. Monoclonal antibodies against the extracellular domain of the human growth factor receptors, 2, 3, and 4, have been raised, and specific and sensitive immunoassays have been established. Sera from healthy individuals (Nordic Reference Interval Project and Database) were analyzed in the human epidermal growth factor receptor 2 assay (N = 805) and the human epidermal growth factor receptor 3 and 4 assays (N = 114), and reference limits were calculated. In addition, sera from 208 individual patients with breast cancer were tested in all three assays. Finally, the human epidermal growth factor receptor 2 assay was compared with a chemiluminescent immunoassay for serum human epidermal growth factor receptor 2/neu. Reference values were as follows: human epidermal growth factor receptor 2, <2.5 µg/L; human epidermal growth factor receptor 3, <2.8 µg/L; and human epidermal growth factor receptor 4, <1.8 µg/L. There were significant differences in human epidermal growth factor receptor 2 and human epidermal growth factor receptor 3 serum levels between the patients with tissue human epidermal growth factor receptor 2-positive and tissue human epidermal growth factor receptor 2-negative ( p = 0.0026, p = 0.000011) tumors, but not in the serum levels of human epidermal growth factor receptor 4 ( p = 0.054). There was good agreement between the in-house human epidermal growth factor receptor 2 assay and the chemiluminescent immunoassay. Our new specific antibodies for all the three human epidermal growth factor receptors may prove valuable in the development of novel anti-human epidermal growth factor receptor targeted therapies with sensitive immunoassays for measuring serum levels of the respective targets and in monitoring established treatment.
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Affiliation(s)
| | - Arne Westgaard
- 2 Department of Oncology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway
| | - Elisabeth Paus
- 1 Department of Medical Biochemistry, Radiumhospitalet, Oslo University Hospital, Oslo, Norway
| | - Miriam Øijordsbakken
- 1 Department of Medical Biochemistry, Radiumhospitalet, Oslo University Hospital, Oslo, Norway
| | - Karoline J Henanger
- 1 Department of Medical Biochemistry, Radiumhospitalet, Oslo University Hospital, Oslo, Norway
| | - Bjørn Naume
- 2 Department of Oncology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway.,3 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Trine Bjøro
- 1 Department of Medical Biochemistry, Radiumhospitalet, Oslo University Hospital, Oslo, Norway.,3 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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López CS, Bouchet-Marquis C, Arthur CP, Riesterer JL, Heiss G, Thibault G, Pullan L, Kwon S, Gray JW. A fully integrated, three-dimensional fluorescence to electron microscopy correlative workflow. Methods Cell Biol 2017; 140:149-164. [PMID: 28528631 DOI: 10.1016/bs.mcb.2017.03.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
While fluorescence microscopy provides tools for highly specific labeling and sensitive detection, its resolution limit and lack of general contrast has hindered studies of cellular structure and protein localization. Recent advances in correlative light and electron microscopy (CLEM), including the fully integrated CLEM workflow instrument, the FEI CorrSight with MAPS, have allowed for a more reliable, reproducible, and quicker approach to correlate three-dimensional time-lapse confocal fluorescence data, with three-dimensional focused ion beam-scanning electron microscopy data. Here we demonstrate the entire integrated CLEM workflow using fluorescently tagged MCF7 breast cancer cells.
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Affiliation(s)
- Claudia S López
- Oregon Health and Sciences University, Portland, OR, United States
| | | | - Christopher P Arthur
- Thermo Fisher Scientific, Hillsboro, OR, United States; Genentech, San Francisco, CA, United States
| | | | - Gregor Heiss
- Thermo Fisher Scientific, Hillsboro, OR, United States
| | | | - Lee Pullan
- Thermo Fisher Scientific, Hillsboro, OR, United States
| | - Sunjong Kwon
- Oregon Health and Sciences University, Portland, OR, United States
| | - Joe W Gray
- Oregon Health and Sciences University, Portland, OR, United States
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47
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Wimana Z, Gebhart G, Guiot T, Vanderlinden B, Larsimont D, Doumont G, Van Simaeys G, Goldman S, Flamen P, Ghanem G. N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging. Oncotarget 2017; 8:56185-56198. [PMID: 28915583 PMCID: PMC5593554 DOI: 10.18632/oncotarget.17015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 03/30/2017] [Indexed: 12/13/2022] Open
Abstract
Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.
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Affiliation(s)
- Zéna Wimana
- Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.,Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Geraldine Gebhart
- Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Thomas Guiot
- Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Bruno Vanderlinden
- Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Denis Larsimont
- Pathology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Gilles Doumont
- Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Brussels, Belgium
| | - Gaetan Van Simaeys
- Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Brussels, Belgium
| | - Serge Goldman
- Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Brussels, Belgium
| | - Patrick Flamen
- Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Ghanem Ghanem
- Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.,Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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48
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Adamczyk A, Grela-Wojewoda A, Domagała-Haduch M, Ambicka A, Harazin-Lechowska A, Janecka A, Cedrych I, Majchrzyk K, Kruczak A, Ryś J, Niemiec J. Proteins Involved in HER2 Signalling Pathway, Their Relations and Influence on Metastasis-Free Survival in HER2-Positive Breast Cancer Patients Treated with Trastuzumab in Adjuvant Setting. J Cancer 2017; 8:131-139. [PMID: 28123607 PMCID: PMC5264049 DOI: 10.7150/jca.16239] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 09/19/2016] [Indexed: 11/18/2022] Open
Abstract
Aim: Resistance to trastuzumab (which is a standard therapy for breast cancer patients with HER2 overexpression) is associated with higher risk of progression or cancer death, and might be related to activation of signalling cascades (PI3K/AKT/mTOR, Ras/Raf/MAPK) and decreased level of their inhibitors. Material and methods: Formalin-fixed paraffin-embedded tumour specimens from 118 HER2-overexpressing breast cancer patients treated with radical local therapy and trastuzumab in adjuvant setting were used for the assessment of: (1) PIK3CA gene mutations (p.H1047R and p.E545K) by qPCR, and (2) expression of Ki-67, EGFR, MUC4, HER3 and PTEN by immunohistochemistry. Results: Lower Ki-67LI was observed in EGFR-immunonegative and in PTEN-immunopositive tumours. MUC4-immunonegative tumours more frequently were PTEN- and HER3-immunonegative. Favourable metastasis-free survival was observed in patients with tumours characterized by Ki-67LI≤50% (p=0.027), HER3 immunonegativity or PTEN immunopositivity (vs. tumours with HER3 expression and lack of PTEN expression, p=0.043), additionally, the trend was observed for patients with pN0+pN1 pathological tumour stage (vs. pN2+pN3) (p=0.086). Cox model revealed that independent negative prognostic factors were: (i) Ki-67LI>50% (p=0.014, RR=4.6, 95% CI 1.4-15.4), (ii) HER3 immunopositivity together with PTEN immunonegativity (p=0.034, RR=3.7, 95% CI 1.1-12.5). Conclusion: The results of our study suggest that combined analysis of HER3 and PTEN expression might bring information on trastuzumab sensitivity in the group of HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting.
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Affiliation(s)
- Agnieszka Adamczyk
- Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Aleksandra Grela-Wojewoda
- Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Małgorzata Domagała-Haduch
- Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Aleksandra Ambicka
- Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Agnieszka Harazin-Lechowska
- Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Anna Janecka
- Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Ida Cedrych
- Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Kaja Majchrzyk
- Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Anna Kruczak
- Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Janusz Ryś
- Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
| | - Joanna Niemiec
- Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland
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49
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Anti-HER2 Therapies in the Adjuvant and Advanced Disease Settings. Breast Cancer 2017. [DOI: 10.1007/978-3-319-48848-6_47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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50
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Tiwari SR, Mishra P, Abraham J. Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. Clin Breast Cancer 2016; 16:344-348. [DOI: 10.1016/j.clbc.2016.05.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 05/17/2016] [Accepted: 05/23/2016] [Indexed: 11/17/2022]
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