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

## TL;DR

A new combination therapy targeting ERBB and Aurora kinases shows promise in treating KRAS-mutated lung cancer and overcoming drug resistance.

## Contribution

Identifies Aurora kinase inhibitors as effective enhancers of afatinib in KRAS-mutant lung adenocarcinoma models.

## Key findings

- ERBB and Aurora kinase co-inhibition suppresses tumor growth and induces apoptosis in KRAS-mutant LUAD models.
- Dual inhibition disrupts compensatory signaling pathways and overcomes resistance to afatinib and sotorasib.
- Phospho-proteomic and transcriptomic analyses confirm activation of pro-apoptotic programs and impairment of survival pathways.

## 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, G2 → 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.