Mutant KRAS‐m 6 A Epitranscriptome Axis Promotes Colorectal Cancer and is a Therapeutic Target

作者：Danyu Chen, Pingmei Huang, Ruizhi Tao, Fenfen Ji, Qinyao Wei, Lok Hin Ko, Lianxin Zhou, Huarong Chen, Alvin Cheung, Wei Kang, Ka‐Fai To, Jun Yu, Chi Chun Wong · 发表于：Advanced Science · 年份：2026 · DOI：10.1002/advs.77627 · 研究领域：RNA modifications and cancer、Ubiquitin and proteasome pathways、Cancer-related gene regulation

ABSTRACT The interaction between gene mutations and epitranscriptomic alterations in colorectal cancer (CRC) remains poorly understood. Here, we identified that KRAS mutations, present in ∼40%–50% of CRC patients, act as driver mutations mediating an aberrant epitranscriptome. In human CRC patients, mutant KRAS correlates with increased m 6 A mRNA modification. In isogenic CRC cells and animal models expressing wild‐type KRAS or mutant KRAS, m 6 A modification was upregulated in mutant KRAS cells/mice. Mutant KRAS promotes m 6 A modification by stabilizing METTL3 protein, an m 6 A writer, through inhibiting its degradation via p62‐driven selective autophagy. Integrative RNA‐seq, m 6 A‐seq, and RIP‐seq revealed BCL9L as a target of mutant KRAS‐mediated m 6 A. Mutant KRAS promotes METTL3‐dependent BCL9L m 6 A modification and YTHDF1‐dependent translation, leading to elevated BCL9L translation and protein expression. Mechanistically, the METTL3‐m 6 A‐BCL9L axis promotes secretion of TGF‐β1/β2/β3 to enrich immunosuppressive T reg in the tumor microenvironment. BCL9L knockout thus significantly impaired KRAS‐mutant CRC growth in murine allograft models and human xenografts in CD34 + immunohumanized mice, concomitant with T reg suppression and Th1 activation. Finally, we demonstrated that pharmacological blockade of METTL3 by STC‐15 or STM2457 synergized with mutant KRAS inhibitors to inhibit KRAS‐mutant CRC growth in mouse models, indicating a promising strategy to boost the effic...