Overcoming Osimertinib Resistance in EGFR-Mutant NSCLC Through GSK-3 Inhibition

Introduction

Non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations initially respond well to first-generation EGFR-TKIs like gefitinib and erlotinib. However, resistance, often due to the EGFR-T790M mutation, develops in most cases. Osimertinib, a third-generation EGFR-TKI, targets these mutations but resistance still emerges through mechanisms including EMT.

Study Findings

Researchers established EGFR-mutant lung cancer cells with EMT-associated osimertinib resistance. They found that downregulation of miR-200c led to EMT induction in these cells. Quisinostat, an HDAC inhibitor, reversed EMT and restored osimertinib sensitivity in most resistant cells. However, for cells where EMT was not controlled by the miR-200c/ZEB1 axis, GSK-3 inhibition was effective. Specifically, the GSK-3α/β inhibitor LY2090314 suppressed growth and induced apoptosis in resistant cells with a mesenchymal phenotype.

Implications

This study suggests that GSK-3 inhibition could be a valuable strategy to overcome EMT-associated resistance to osimertinib in EGFR-mutant NSCLC. The findings highlight the importance of targeting mesenchymal-specific survival signaling and offer hope for patients with acquired resistance to EGFR-TKIs.