Abstract

The efficacy of gefitinib and sotorasib in EGFR- and KRAS mutant non-small cell lung cancer (NSCLC) is limited by rapid drug resistance. Conventional strategies targeting emerging mutations are time-consuming and often yield additional resistance. Here, we identify a shared, mutation-independent resistance mechanism, dysregulated efferocytosis that operates independently of direct receptor signaling. Through multidatabase screening, we identified the natural flavonoid galangin as a potent therapeutic sensitizer. In vivo, galangin significantly restored tumor sensitivity to both gefitinib and sotorasib. Transcriptomic profiling further revealed that galangin reverses sotorasib resistance by modulating the efferocytosis pathway. Mechanistically, galangin suppressed M2 macrophage polarization, directly interacted with the efferocytosis-related targets CAMK2A and MERTK, and reduced their expression. Together, these findings establish efferocytosis as a novel and targetable vulnerability in drug-resistant NSCLC and highlight galangin as a promising sensitizer for overcoming resistance to two major targeted therapies.