Abstract
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.
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The authors thank all the patients who donated samples for this study.
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This study was funded by the National Key Research and Development Program of China (No.2022YFA1304000), National Natural Science Foundation of China (82320108015, 82170188, 82470143, 8257115431 and 8250114178), Guangzhou Science and Technology Program (2023B01J1004), Guangdong Provincial Key Areas R&D Program (2023B1111040003) and National Key Clinical Discipline.
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Guo, Y., Zhong, Y., Hu, P. et al. Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73805-7
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DOI: https://doi.org/10.1038/s41467-026-73805-7
