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<p>The emergence of covalent KRAS<sup>G12C</sup> 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<sup>G12C</sup> 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<sup>G12C</sup> 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<sup>G12C</sup> inhibitor resistance and support repurposing statins to improve KRAS<sup>G12C</sup>-targeted therapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Weihao Lin,
  • Qi-an Chen,
  • Yannan Yang,
  • Yibo Gao,
  • Jie He

摘要

The emergence of covalent KRASG12C 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 KRASG12C 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 KRASG12C 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 KRASG12C inhibitor resistance and support repurposing statins to improve KRASG12C-targeted therapy.