Identification of HGF/c-MET as a biomarker of resistance to Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitors

Therapeutic resistance to VEGFR signaling inhibitors is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). We investigated the contribution of stromal and tumor cells to resistance of NSCLC to VEGFR tyrosine kinase inhibitors (TKIs). Gene expression analysis of stromal (mouse) and tumor (human) compartments enabled us to identify the HGF/c-MET pathway as a driver and a potential biomarker of VEGFR TKI resistance. Murine models of human NSCLC were generated and targeted inhibition studies were performed using AZD2171 (cediranib) and ZD6474 (vandetanib). Species-specific transcriptomic profiling was applied to NSCLC xenografts that were sensitive or resistant to therapy.