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<p>KRAS inhibitors (KRASi) have emerged as promising new cancer therapeutics for KRAS-mutant cancers; however, resistance remains a potential clinical challenge. Here, we show that reactivation of ERK is a hallmark of KRASi-resistant colorectal cancers (CRCs) and further demonstrate that enhancer remodeling rewires cholesterol biosynthesis through the mevalonate (MVA) pathway to confer this resistance. Mechanistically, enhancer remodeling activates MVA pathway, which facilitates the trafficking of KRAS to the membrane and sustains the MAPK signaling despite KRAS inhibition. Pharmacological inhibition of the MVA pathway with statins effectively blocks KRAS localization to the cell membrane, overcoming KRASi resistance in CRC. Together, these findings identify epigenetic-metabolic coupling of cholesterol biosynthesis as a mechanism of KRASi resistance and highlight targetable metabolic vulnerability in KRAS-mutant CRC.</p>

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Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Yaoyu Guo,
  • Yi Zhong,
  • Peishan Hu,
  • Yufeng Chen,
  • Wenjun Guo,
  • Jianfeng Chen,
  • Peiyong Guan,
  • Zhengran Zhou,
  • Fang Zhu,
  • Xian Zeng,
  • Jiuping Gao,
  • Qiqing Xiong,
  • Zhaoliang Yu,
  • Chuling Hu,
  • Zerong Cai,
  • Xiaoyu Xie,
  • Jing Han Hong,
  • Jason Yongsheng Chan,
  • Wenyu Wang,
  • Dechang Diao,
  • Xiaojun Xia,
  • Qiang Yu,
  • Choon Kiat Ong,
  • Yijun Gao,
  • Xiaojian Wu,
  • Jing Tan

摘要

KRAS inhibitors (KRASi) have emerged as promising new cancer therapeutics for KRAS-mutant cancers; however, resistance remains a potential clinical challenge. Here, we show that reactivation of ERK is a hallmark of KRASi-resistant colorectal cancers (CRCs) and further demonstrate that enhancer remodeling rewires cholesterol biosynthesis through the mevalonate (MVA) pathway to confer this resistance. Mechanistically, enhancer remodeling activates MVA pathway, which facilitates the trafficking of KRAS to the membrane and sustains the MAPK signaling despite KRAS inhibition. Pharmacological inhibition of the MVA pathway with statins effectively blocks KRAS localization to the cell membrane, overcoming KRASi resistance in CRC. Together, these findings identify epigenetic-metabolic coupling of cholesterol biosynthesis as a mechanism of KRASi resistance and highlight targetable metabolic vulnerability in KRAS-mutant CRC.