Mutant KRAS-m⁶A Epitranscriptome Axis Promotes Colorectal Cancer and is a Therapeutic Target.

Authors

Danyu Chen, Pingmei Huang, Ruizhi Tao, Fenfen Ji, Qinyao Wei, Lok Hin Ko, Lianxin Zhou, Huarong Chen, Alvin Cheung, Wei Kang, Ko Fai To, Jun Yu, Chi Chun Wong

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77627. Sep 09, 2026. Epub Sep 09, 2026.

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 m⁶A mRNA modification. In isogenic CRC cells and animal models expressing wild-type KRAS or mutant KRAS, m⁶A modification was upregulated in mutant KRAS cells/mice. Mutant KRAS promotes m⁶A modification by stabilizing METTL3 protein, an m⁶A writer, through inhibiting its degradation via p62-driven selective autophagy. Integrative RNA-seq, m⁶A-seq, and RIP-seq revealed BCL9L as a target of mutant KRAS-mediated m⁶A. Mutant KRAS promotes METTL3-dependent BCL9L m⁶A modification and YTHDF1-dependent translation, leading to elevated BCL9L translation and protein expression. Mechanistically, the METTL3-m⁶A-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 efficacy of KRAS inhibitors in KRAS-mutant CRC.

PMID:
42717493
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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