PIKing up and AKTing on Resistance Mutations in Osimertinib-Treated EGFR-Mutated NSCLC

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Osimertinib is a targeted therapy for EGFR-mutated non-small cell lung cancer (NSCLC).
• PI3K-AKT pathway mutations are increasingly recognized as a mechanism of resistance to EGFR inhibitors.
• Understanding resistance mechanisms is crucial for improving NSCLC treatment outcomes.

Purpose of the Study:

• To investigate the prevalence and impact of PI3K-AKT pathway mutations on osimertinib sensitivity in EGFR-mutated NSCLC.
• To evaluate the efficacy of the AKT inhibitor capivasertib in overcoming osimertinib resistance driven by these mutations.

Main Methods:

• Analysis of mutation data from the FLAURA and AURA3 osimertinib clinical trials.
• Pre-clinical validation of identified mutations and their effect on osimertinib sensitivity.
• In vitro and in vivo studies assessing the anti-tumor activity of capivasertib in resistant models.

Main Results:

• High rates of PI3K-AKT pathway mutations were identified in patients treated with osimertinib.
• These mutations were pre-clinically validated to confer resistance to osimertinib in EGFR-mutated NSCLC.
• Capivasertib effectively overcame osimertinib resistance in pre-clinical models.

Conclusions:

• PI3K-AKT pathway activation is a significant mechanism of osimertinib resistance in EGFR-mutated NSCLC.
• Targeting the AKT pathway with inhibitors like capivasertib represents a promising therapeutic strategy for resistant NSCLC.
• Further clinical investigation of AKT inhibitors in combination with or after osimertinib is warranted.