Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-020-15318-5
Title: A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma
Authors: Kong, Li Ren 
Salleh, Nur Afiqah Binte Mohamed 
Ong, Richard Weijie
Tan, Tuan Zea 
Syn, Nicholas L
Goh, Robby Miguel
Fhu, Chee Wei 
Tan, Daniel SW 
Iyer, N Gopalakrishna 
Kannan, Srinivasaraghavan
Verma, Chandra S 
Lim, Yaw Chyn 
Soo, Ross 
Ho, Jingshan 
Huang, Yiqing
Lim, Joline SJ 
Yan, Benedict Junrong
Nga, Min En 
Lim, Seng Gee 
Koeffler, H Phillip 
Lee, Soo Chin 
Kappei, Dennis 
Hung, Huynh The 
Goh, Boon Cher 
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
HEPATOCYTE GROWTH-FACTOR
SCATTER FACTOR
C-MET
SEMA DOMAIN
RECEPTOR
METASTASIS
HEAD
RESISTANCE
MUTATIONS
REVEALS
Issue Date: 25-Mar-2020
Publisher: NATURE PUBLISHING GROUP
Citation: Kong, Li Ren, Salleh, Nur Afiqah Binte Mohamed, Ong, Richard Weijie, Tan, Tuan Zea, Syn, Nicholas L, Goh, Robby Miguel, Fhu, Chee Wei, Tan, Daniel SW, Iyer, N Gopalakrishna, Kannan, Srinivasaraghavan, Verma, Chandra S, Lim, Yaw Chyn, Soo, Ross, Ho, Jingshan, Huang, Yiqing, Lim, Joline SJ, Yan, Benedict Junrong, Nga, Min En, Lim, Seng Gee, Koeffler, H Phillip, Lee, Soo Chin, Kappei, Dennis, Hung, Huynh The, Goh, Boon Cher (2020-03-25). A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma. NATURE COMMUNICATIONS 11 (1). ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-020-15318-5
Abstract: © 2020, The Author(s). 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.
Source Title: NATURE COMMUNICATIONS
URI: https://scholarbank.nus.edu.sg/handle/10635/175475
ISSN: 20411723
DOI: 10.1038/s41467-020-15318-5
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