Molecular Mechanisms of EGFR-TKI Resistance and Strategy with HGF-MET Inhibitors to Overcome the Resistance

Dramatic response has been achieved with EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib), in EGFR mutant lung cancer. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to EGFR-TKIs include gatekeeper mutations in EGFR and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand-triggered receptor activation as well. For example, hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells. These observations indicate that signals from oncogenic drivers (EGFR signaling) and ligand-triggered bypass signals (HGF-Met) must be simultaneously blocked to avoid the resistance. This talk will focus specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies using HGF-Met inhibitors that are under development for overcoming resistance to EGFR-TKIs in lung cancer.