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

AI Article Synopsis

  • c-MET receptors in cancers can be activated by mutations and amplifications, but can be targeted by small molecule inhibitors.
  • A common genetic variant (N375S) enhances the binding of MET to HER2, leading to a dimer that promotes aggressive cancer behavior.
  • HER2 inhibitors, rather than c-MET inhibitors, are more effective in reducing cancer growth in models with elevated MET, suggesting a new therapeutic target for certain squamous cell carcinomas.

Article 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 MET to interact with HER2 in a ligand-independent fashion. The resultant MET/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. These results establish MET as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096530PMC
http://dx.doi.org/10.1038/s41467-020-15318-5DOI Listing

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