Journal Article

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

Soo, Ross, Lim, Seng Gee, Kappei, Dennis, Kannan, Srinivasaraghavan, Huang, Yiqing, Yan, Benedict Junrong, Kong, Li Ren, Tan, Tuan Zea, Koeffler, H. Phillip, Syn, Nicholas L., Verma, Chandra S., Lim, Yaw Chyn, Fhu, Chee Wai, Tan, Daniel S. W., Mohamed Salleh, Nur Afiqah Binte, Ong, Richard Weijie, Lim, Joline S. J., Nga, Min En, Lee, Soo Chin, Iyer, N. Gopalakrishna, Hung, Huynh The, Goh, Robby Miguel, Ho, Jingshan, Goh, Boon Cher

2020

Overview

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 MET N375S to interact with HER2 in a ligand-independent fashion. The resultant MET N375S /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 MET N375S . These results establish MET N375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies. The MET receptor is frequently activated in cancer. Here, the authors show that in head and neck and lung squamous carcinoma, a polymorphic MET variant enhances binding to HER2, resulting in activation of HER2 signalling and progression of the cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/105 / 13/106 / 13/109 / 13/51 / 13/89 / 14 / 14/19 / 14/32 / 14/63 / 38 / 38/23 / 38/39 / 42 / 42/70 / 45 / 45/77 / 631/337/475/2290 / 631/67/1059/602 / 631/80/86/820 / 64 / 64/60 / 692/4028/67/1536 / 82/29 / 82/58 / 82/79 / 96 / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Binding / c-Met protein / Cancer / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - mortality / Carcinoma, Squamous Cell - pathology / Cell Line, Tumor / Dimers / Domains / ErbB-2 protein / Gene polymorphism / Harnesses / Head & neck cancer / Head and neck carcinoma / Head and Neck Neoplasms - drug therapy / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - mortality / Head and Neck Neoplasms - pathology / Humanities and Social Sciences / Humans / Inhibitors / Invasiveness / Kinases / Lung cancer / Lung carcinoma / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - mortality / Lung Neoplasms - pathology / Lungs / MET protein / Metastases / Mice / multidisciplinary / Mutation / Phenotype / Phosphorylation - drug effects / Polymorphism / Polymorphism, Genetic / Prognosis / Protein Binding / Protein Interaction Domains and Motifs / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase / Proto-Oncogene Proteins c-met - chemistry / Proto-Oncogene Proteins c-met - genetics / Proto-Oncogene Proteins c-met - metabolism / Receptor, ErbB-2 - antagonists & inhibitors / Receptor, ErbB-2 - metabolism / Receptors / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Signaling / Splicing / Squamous cell carcinoma / Tyrosine / Xenograft Model Antitumor Assays