The Third-Generation EGFR Inhibitor, Osimertinib, Promotes c-FLIP Degradation, Enhancing Apoptosis Including TRAIL-Induced Apoptosis in NSCLC Cells with Activating EGFR Mutations

Abstract

The third-generation EGFR inhibitor, osimertinib (AZD9291), selectively and irreversibly inhibits EGFR activating and T790 M mutants while sparing wild-type EGFR. Osimertinib is now an approved drug for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (first-line) or those who have become resistant to 1st generation EGFR inhibitors through the T790 M mutation (second-line). Unfortunately, all patients eventually relapse and develop resistance to osimertinib. Hence, it is essential to fully understand the biology underlying the development of resistance to osimertinib in order to improve its therapeutic efficacy and overcome resistance. Cellular FLICE-inhibitory protein (c-FLIP) is a truncated form of caspase-8 and functions as a key inhibitor of the extrinsic apoptotic pathway. The current study has demonstrated that osimertinib reduces c-FLIP levels via facilitating its degradation and enhances apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) primarily in NSCLC with activating EGFR mutations. Moreover, modulation of c-FLIP expression levels, to some degree, also alters the sensitivities of EGFR mutant NSCLC cells to undergo osimertinib-induced apoptosis, suggesting that c-FLIP suppression is an important event contributing to the antitumor activity of osimertinib against EGFR mutant NSCLC.