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 Treg 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 Treg 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.