Abstract
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.
Highlights
Human formalin-fixed paraffin-embedded (FFPE) tumor specimens and tissue microarrays were obtained from Department of Pathology, National University Hospital (NUH, Singapore), as well as from patients who have undergone surgical resection at NUH
To model possible modes of interactions between c-MET and HER2, we utilized the program CLICK to compare structural regions between two different proteins, irrespective of sequence similarity. This search was performed on the conformations of METwt and METN375S that were generated during the molecular dynamics (MD) simulations
(A-D) Cell invasion and colony forming assays were performed on isogenic LUSC (Calu-1) and HNSCC (SCC13, UMSCC1) cells transfected with empty vector (EV), wild-type (METwt-tGFP) and N375S mutant (METN375S-tGFP)
Summary
This search was performed on the conformations of METwt and METN375S that were generated during the MD simulations. (A-D) Cell invasion and colony forming assays were performed on isogenic LUSC (Calu-1) and HNSCC (SCC13, UMSCC1) cells transfected with empty vector (EV), wild-type (METwt-tGFP) and N375S mutant (METN375S-tGFP). Immunoblots demonstrated expression levels of total and phosphorylated MET were shown (far right).
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