A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

Li Ren Kong (), Nur Afiqah Binte Mohamed Salleh, Richard Weijie Ong, Tuan Zea Tan, Nicholas L. Syn, Robby Miguel Goh, Chee Wai Fhu, Daniel S. W. Tan, N. Gopalakrishna Iyer, Srinivasaraghavan Kannan, Chandra S. Verma, Yaw Chyn Lim, Ross Soo, Jingshan Ho, Yiqing Huang, Joline S. J. Lim, Benedict Junrong Yan, Min En Nga, Seng Gee Lim, H. Phillip Koeffler, Soo Chin Lee, Dennis Kappei, Huynh The Hung and Boon Cher Goh ()
Additional contact information
Li Ren Kong: National University of Singapore
Nur Afiqah Binte Mohamed Salleh: National University of Singapore
Richard Weijie Ong: National Cancer Centre Singapore
Tuan Zea Tan: National University of Singapore
Nicholas L. Syn: National University of Singapore
Robby Miguel Goh: National University Cancer Institute
Chee Wai Fhu: National University of Singapore
Daniel S. W. Tan: Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore
N. Gopalakrishna Iyer: National University of Singapore
Srinivasaraghavan Kannan: Technology, and Research (A*STAR)
Chandra S. Verma: Technology, and Research (A*STAR)
Yaw Chyn Lim: National University Health System
Ross Soo: National University Cancer Institute
Jingshan Ho: National University Cancer Institute
Yiqing Huang: National University Cancer Institute
Joline S. J. Lim: National University of Singapore
Benedict Junrong Yan: National University Health System
Min En Nga: National University Health System
Seng Gee Lim: National University of Singapore
H. Phillip Koeffler: National University of Singapore
Soo Chin Lee: National University of Singapore
Dennis Kappei: National University of Singapore
Huynh The Hung: National Cancer Centre Singapore
Boon Cher Goh: National University of Singapore

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover 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 interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer 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. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

Date: 2020
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DOI: 10.1038/s41467-020-15318-5

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