Kong, L.R., Mohamed Salleh, N.A.B., Ong, R.W. et al. A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma. Nat Commun 11, 1556 (2020). https://doi.org/10.1038/s41467-020-15318-5
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.
This work was funded by the Singapore Ministry of Health’s National Medical Research Council (NMRC/CSA-SI/0006/2016), the National Research Foundation (NRF) Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (Boon-Cher Goh); as well as to Boon-Cher Goh and Li-Ren Kong by Singapore Ministry of Health’s National Medical Research Council under its NCIS Centre Grant (NMRC/CG/012/2013). Chandra S Verma and Srinivasaraghavan Kannan thank A*STAR, NRF and Singapore Economic Development Board for grant support.