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

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.