HGF-MET in Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic effects against non-small cell lung cancer (NSCLC) with EGFR activating mutations. However, 25%-30% of EGFR mutant lung cancer patients show intrinsic resistance, and the responders almost invariably acquire resistance to EGFR-TKIs within several years. Three mechanisms—second-site point mutation that substitutes methionine for threonine at position 790 (T790M) in EGFR, amplification of MET protooncogene, and overexpression of hepatocyte growth factor (HGF, a ligand of MET)—have been reported to contribute to resistance to EGFR-TKIs. These three factors were detected simultaneously in a population of patients with acquired resistance to EGFR-TKIs. Further investigations to develop optimal therapy based on accurate diagnosis of resistant mechanism are warranted to improve the prognosis of EGFR mutant lung cancer.