KRAS mutated lung adenocarcinoma responds to pan-ERBB and Aurora kinase inhibitors

Abstract KRAS mutations are prevalent in lung adenocarcinoma (LUAD). Although KRAS-targeted therapies such as KRAS-G12C inhibitor sotorasib are now clinically available, their durability is limited by rapid resistance development, underscoring the need for novel strategies. Through high-throughput drug screening, we identified Aurora kinase (AURK) inhibitors as potent enhancers of afatinib efficacy in KRAS mutant LUAD models. ERBB/AURK co-inhibition synergized to suppress cell viability, clonogenicity, and tumor growth, mediated by induction of apoptosis, G 2 → M cell cycle arrest, and disruption of compensatory signaling pathways. Mechanistically, dual inhibition activated pro-apoptotic programs, while impairing mitotic and survival pathways, as confirmed by phospho-proteomic and transcriptomic analyses. Notably, co-targeting ERBB and AURK effectively overcame resistance in afatinib- and sotorasib-refractory models, wherein bypass activation of EGFR, ERK, and AURK was observed. Given the limited survival benefit associated with KRAS-targeted therapies and rapid emergence of resistance in clinical settings, our findings establish ERBB/AURK co-inhibition as a promising therapeutic strategy to improve durability of response and combat acquired resistance in KRAS driven LUAD.