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A Common Met Polymorphism Harnesses Her2 Signaling to Drive Aggressive Squamous Cell Carcinoma

64 Pages Posted: 2 Mar 2019 Last revised: 29 May 2019 Sneak Peek Status: Review Complete

See all articles by Li Ren Kong

Li Ren Kong

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Nur Afiqah Binte Mohamed Salleh

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Richard Weijie Ong

National Cancer Centre Singapore - Laboratory of Molecular Endocrinology

Tuan Zea Tan

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Nicholas L. Syn

National University of Singapore (NUS) - Cancer Science Institute of Singapore; National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Robby Miguel Goh

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Daniel S. W. Tan

National Cancer Centre Singapore - Cancer Therapeutics Research Laboratory; Agency for Science, Technology & Research (A*STAR) - Genome Institute of Singapore

N. Gopalakrishna Iyer

National University of Singapore (NUS) - Cancer Science Institute of Singapore; National University of Singapore (NUS), Duke-NUS Graduate Medical School Singapore, Office of Clinical Sciences; National Cancer Centre Singapore - Division of Surgical Oncology

Yaw Chyn Lim

National University Health System (NUHS) - Department of Pathology

Ross Soo

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Jingshan Ho

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Yiqing Huang

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Joline S. J. Lim

National University of Singapore (NUS) - Cancer Science Institute of Singapore; National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Benedict Junrong Yan

National University Health System (NUHS) - Department of Pathology

Min En Nga

National University Health System (NUHS) - Department of Pathology

Seng Gee Lim

National University of Singapore (NUS), Yong Loo Lin School of Medicine, Department of Medicine; National University Health System (NUHS) - Division of Gastroenterology and Hepatology

H. Phillip Koeffler

National University of Singapore (NUS) - Cancer Science Institute of Singapore; National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology; National University of Singapore (NUS), Yong Loo Lin School of Medicine, Department of Medicine; Cedars-Sinai Medical Center - Department of Hematology and Oncology

Soo Chin Lee

National University of Singapore (NUS) - Cancer Science Institute of Singapore; National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Dennis Kappei

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Huynh The Hung

National Cancer Centre Singapore - Laboratory of Molecular Endocrinology

Boon Cher Goh

National University of Singapore (NUS) - Cancer Science Institute of Singapore; National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology; National University of Singapore (NUS), Yong Loo Lin School of Medicine, Department of Pharmacology

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Abstract

Upfront resistance to c-Met inhibitors currently in clinical development is ubiquitous and poorly understood. We discovered that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to heterodimerize with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 heterodimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-Met inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. Clinical proof-of-concept is afforded by radiological and biochemical responses observed in two METN375S-heterozygous patients with refractory HNSCC whom we successfully treated with HER2 inhibitors. These results establish METN375S as a biologically-distinct and clinically-actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

Suggested Citation

Kong, Li Ren and Salleh, Nur Afiqah Binte Mohamed and Ong, Richard Weijie and Tan, Tuan Zea and Syn, Nicholas L. and Goh, Robby Miguel and Tan, Daniel S. W. and Iyer, N. Gopalakrishna and Lim, Yaw Chyn and Soo, Ross and Ho, Jingshan and Huang, Yiqing and Lim, Joline S. J. and Yan, Benedict Junrong and Nga, Min En and Lim, Seng Gee and Koeffler, H. Phillip and Lee, Soo Chin and Kappei, Dennis and Hung, Huynh The and Goh, Boon Cher, A Common Met Polymorphism Harnesses Her2 Signaling to Drive Aggressive Squamous Cell Carcinoma (March 2, 2019). Available at SSRN: https://ssrn.com/abstract=3345544 or http://dx.doi.org/10.2139/ssrn.3345544
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Li Ren Kong

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

Nur Afiqah Binte Mohamed Salleh

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

Richard Weijie Ong

National Cancer Centre Singapore - Laboratory of Molecular Endocrinology

Singapore

Tuan Zea Tan

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

Nicholas L. Syn

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

Robby Miguel Goh

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

Daniel S. W. Tan

National Cancer Centre Singapore - Cancer Therapeutics Research Laboratory

Singapore

Agency for Science, Technology & Research (A*STAR) - Genome Institute of Singapore

60 Biopolis St
138672
Singapore

N. Gopalakrishna Iyer

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

National University of Singapore (NUS), Duke-NUS Graduate Medical School Singapore, Office of Clinical Sciences

Singapore

National Cancer Centre Singapore - Division of Surgical Oncology

Singapore

Yaw Chyn Lim

National University Health System (NUHS) - Department of Pathology

Singapore

Ross Soo

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

Jingshan Ho

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

Yiqing Huang

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

Joline S. J. Lim

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

Benedict Junrong Yan

National University Health System (NUHS) - Department of Pathology

Singapore

Min En Nga

National University Health System (NUHS) - Department of Pathology

Singapore

Seng Gee Lim

National University of Singapore (NUS), Yong Loo Lin School of Medicine, Department of Medicine

Singapore

National University Health System (NUHS) - Division of Gastroenterology and Hepatology

Singapore

H. Phillip Koeffler

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

National University of Singapore (NUS), Yong Loo Lin School of Medicine, Department of Medicine

Singapore

Cedars-Sinai Medical Center - Department of Hematology and Oncology

Los Angeles, CA
United States

Soo Chin Lee

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology

Singapore

Dennis Kappei

National University of Singapore (NUS) - Cancer Science Institute of Singapore

Singapore

Huynh The Hung

National Cancer Centre Singapore - Laboratory of Molecular Endocrinology

Singapore

Boon Cher Goh (Contact Author)

National University of Singapore (NUS) - Cancer Science Institute of Singapore ( email )

Singapore

National University of Singapore (NUS), Cancer Science Institute of Singapore, Department of Haematology-Oncology ( email )

Singapore

National University of Singapore (NUS), Yong Loo Lin School of Medicine, Department of Pharmacology ( email )

Singapore

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