MET–GRB2 signaling-associated complexes correlate with oncogenic MET signaling and sensitivity to MET kinase inhibitors

Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments. Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N ¼ 406) and patient-derived xenograft (PDX) models of solid tumors (N ¼ 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N ¼ 6) and provide a case report of a lung cancer patient harboring a Dexon14 MET splice variant. Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with Dexon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with Dexon14 MET lacking MET gene amplification. Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms.