PDK1 and YAP1/TEAD signaling drive acquired KRAS inhibitor resistance in KRAS-mutant non-small cell lung cancer

Mutations in KRAS are responsible for driving approximately 30% of NSCLC. While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRAS ^G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). However, the efficacy of these inhibitors in the clinics has been limited by primary and acquired means of resistance. To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways. Pharmacological inhibition and genetic loss-of-function studies revealed a strong dependence on these pathways for the generation and maintenance of resistance to KRAS inhibition, which was then validated <i>in vitro</i> and <i>in vivo</i> . Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC.