Targeting the mevalonate pathway with statins overcomes acquired resistance to KRASG12C inhibitors in non-small cell lung cancer

The emergence of covalent KRAS G12C inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC), yet acquired resistance remains a major clinical challenge. Here, we systematically identified statins as potent agents capable of overcoming acquired resistance to KRAS G12C inhibitors through high-throughput screening of 1,971 FDA-approved compounds. Statin treatment preferentially induced cell death in resistant cells, markedly impairing tumor growth both in vitro and in vivo. Proteomic profiling and pathway analysis revealed upregulation of the mevalonate (MVA) pathway in resistant cells. Genetic silencing of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and pharmacologic inhibition of the MVA-geranylgeranyl pyrophosphate (GGPP) branch recapitulated the effects of statins. Mechanistically, MVA-GGPP signaling promoted Yes-associated protein (YAP) activation, whereas disruption of this axis by statins or geranylgeranyl transferase I (GGTase-I) inhibitors impaired YAP-driven transcription and cell survival. Combination therapy with simvastatin and KRAS G12C inhibitors delayed resistance onset and enhanced antitumor efficacy across multiple in vivo models, with acceptable tolerability. These findings identify the MVA-GGPP-YAP pathway as a therapeutic vulnerability in acquired KRAS G12C inhibitor resistance and support repurposing statins to improve KRAS G12C -targeted therapy.