A Common Met Polymorphism Harnesses Her2 Signaling to Drive Aggressive Squamous Cell Carcinoma
64 Pages Posted: 2 Mar 2019 Last revised: 29 May 2019 Sneak Peek Status: Review CompleteMore...
Upfront resistance to c-Met inhibitors currently in clinical development is ubiquitous and poorly understood. We discovered 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 heterodimerize with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 heterodimer 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. Clinical proof-of-concept is afforded by radiological and biochemical responses observed in two METN375S-heterozygous patients with refractory HNSCC whom we successfully treated with HER2 inhibitors. These results establish METN375S as a biologically-distinct and clinically-actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.
Suggested Citation: Suggested Citation