Inhibition of the MEK-ERK signaling pathway reverses acquired osimertinib resistance in NSCLC attributed to AXL overexpression.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard first-line treatment for patients with EGFR-activating mutation of late-stage non-small cell lung cancer (NSCLC), but the emergence of acquired resistance limits its efficacy in real use. The overexpression of anexelekto (AXL) is known to be associated with acquired resistance to osimertinib. However, the specific mechanisms of AXL-mediated resistance are not well explained, nor of the specific therapeutic approaches in patients for this. In this study, we identified that activation of MEK-ERK pathway played a key role in AXL-driven acquired osimertinib resistance in NSCLC. Inhibition of the MEK-ERK activation restored osimertinib sensitivity in AXL-driven resistant tumor cells. The combination use of MEK inhibitor with osimertinib reversed the aquierd osimertinib resistance in vitor and in vivo. Our findings provide preclinical mechanistic support for potential use to targeting MEK-ERK signaling in AXL-associated osimertinib resistance and forfurther validation in patient-derived and clinical models.