A molecular signature for MET-targeted therapy

Constitutive MET signaling promotes invasiveness in primary and recurrent GBM; however, current MET-targeting strategies lack of effective biomarkers for selecting suitable patients for treatment. Here, we identified a predictive signature potentially valuable for indicating vulnerability to MET-targeted therapy in GBM. The use of both human and mouse gene expression microarrays showed that MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall they impede tumor growth by inhibiting cell cycle progression. Notably, GBM tumors with EGFRamp that showed resistance to erlotinib treatment also showed activation of the MET pathway, suggesting that a combination of EGFR and MET inhibitors may overcome or prevent such resistance in patients with EGFRamp GBM. GBM cell lines (DBM2, U251M2, U87M2, U118, and SF295) were treated for 7 days with either vehicle (n=14) or V-4084 (n=14) (i.e. SF295 + vehicle (n=2), SF295 + V-4084 (n=2), U118 + vehicle (n=3), U118 + V-4084 (n=3), U87M2 + vehicle (n=3), U87M2 + V-4084 (n=3), DBM2 + vehicle (n=3), DBM2 + V-4084 (n=3), U251M2 + vehicle (n=3), U251M2 + V-4084 (n=3)). GBM cell lines (DBM2, U251M2, U87M2, U118, and SF295) were subcutaneously inoculated into the flank region of nude mice to initiate tumor growth. Subsequently mice were treated for 7 days with either vehicle (n=14) or V-4084 (n=14) (i.e. SF295 + vehicle (n=2), SF295 + V-4084 (n=3), U118 + vehicle (n=3), U118 + V-4084 (n=3), U87M2 + vehicle (n=3), U87M2 + V-4084 (n=3), DBM2 + vehicle (n=3), DBM2 + V-4084 (n=3), U251M2 + vehicle (n=3), U251M2 + V-4084 (n=2)).