Researchers Identify a New Therapeutic Target for Colorectal Cancer

Recently, researchers published a study entitled “Mutant KRAS-m6A Epitranscriptome Axis Promotes Colorectal Cancer and Is a Therapeutic Target.” The study found that KRAS mutations, which occur in approximately 40%–50% of patients with colorectal cancer (CRC), act as driver mutations that mediate aberrant epitranscriptomic remodeling. In clinical samples from patients with CRC, mutant KRAS was associated with elevated levels of mRNA N6-methyladenosine (m6A) modification. Similarly, m6A levels were significantly increased in mutant KRAS cells and mice compared with their wild-type KRAS counterparts in isogenic CRC cell lines and animal models.

Mutant KRAS stabilized the m6A methyltransferase METTL3 by inhibiting its degradation through p62-mediated selective autophagy, thereby increasing global m6A modification levels. Integrated RNA-seq, m6A-seq, and RIP-seq analyses identified BCL9L as a downstream target of mutant KRAS-regulated m6A modification.

Mutant KRAS promoted METTL3-dependent m6A methylation of BCL9L and enhanced BCL9L translation through YTHDF1, ultimately increasing BCL9L protein expression. Mechanistically, the METTL3-m6A-BCL9L signaling axis promoted the secretion of TGF-β1, TGF-β2, and TGF-β3, resulting in extensive enrichment of immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment.

Tumor transplantation experiments demonstrated that BCL9L knockout significantly inhibited the growth of KRAS-mutant CRC in both murine syngeneic allograft models and xenograft models established in CD34⁺ humanized immune-system mice. This effect was accompanied by reduced Treg infiltration and activation of Th1-type immune responses.

Finally, the study showed that pharmacological inhibition of METTL3 with STC-15 or STM2457 produced synergistic antitumor effects when combined with mutant KRAS inhibitors. These combinations suppressed the progression of KRAS-mutant CRC in mice, providing a promising therapeutic strategy for improving responses to targeted therapies in patients with KRAS-mutant CRC.

The Therapeutic Challenge of KRAS-Mutant Colorectal Cancer

Colorectal cancer is one of the most commonly diagnosed malignancies worldwide and a leading cause of cancer-related death. Despite substantial advances in chemotherapy and molecularly targeted treatment, the prognosis of patients with advanced or metastatic CRC remains poor, with a five-year survival rate below 12%.

Colorectal tumorigenesis is commonly initiated by the inactivation of the tumor suppressor gene APC, which occurs in approximately 90% of cases. KRAS mutations, detected in approximately 40%–50% of patients, often represent a second oncogenic hit that drives the progression of colorectal adenomas into carcinomas.

In addition, KRAS mutations cause primary resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy and are associated with poor responses to immune checkpoint blockade. Effective treatment of KRAS-mutant CRC therefore remains a major unmet clinical need.

Although KRAS has long been recognized as a critical oncogenic driver in CRC, directly targeting the protein has presented a major therapeutic challenge. For several decades, KRAS was widely considered an “undruggable” target. The development of the first KRAS^G12C inhibitors represented a major breakthrough in KRAS-targeted cancer therapy.

However, although KRAS^G12C inhibitors have demonstrated clinical benefits in lung and pancreatic cancers, their response rates in CRC have been less satisfactory. Combination therapy has consequently emerged as an important treatment direction for KRAS-mutant CRC, as illustrated by the recent approval of sotorasib in combination with panitumumab for patients with KRAS^G12C-mutant CRC.

Nevertheless, treatment resistance remains difficult to avoid even when KRAS and EGFR are targeted simultaneously. Developing new strategies that can improve the responsiveness of CRC to KRAS inhibitors is therefore both urgent and clinically important.

Linking Mutant KRAS to m6A Epitranscriptomic Remodeling

The development and progression of CRC result from the combined effects of genetic, epigenetic, and epitranscriptomic alterations. N6-methyladenosine is the most abundant internal modification found in human mRNA and regulates multiple aspects of RNA metabolism, including mRNA splicing, stability, and translational efficiency.

m6A modification is precisely controlled by a coordinated system of regulatory enzymes. It plays a decisive role in cancer by promoting cell proliferation, maintaining stem-like properties, and regulating the tumor microenvironment. Several drug development pipelines have already generated candidate compounds that specifically target regulatory proteins involved in m6A modification, including METTL3. However, the potential interaction between KRAS mutations and m6A modification had not previously been investigated.

This study uncovered a previously unrecognized relationship between mutant KRAS and m6A modification in CRC. Across CRC patient samples, animal models, and CRC cell lines, KRAS mutations were associated with elevated m6A modification and increased expression of the m6A writer protein METTL3.

Mechanistically, mutant KRAS inhibited the autophagic degradation of METTL3, thereby increasing its protein stability. Under normal conditions, p62-mediated selective autophagy contributes to METTL3 degradation. Mutant KRAS disrupted this process, leading to METTL3 accumulation and a corresponding increase in m6A modification.

The researchers further identified BCL9L as a critical downstream effector of the mutant KRAS–METTL3 axis. METTL3-mediated m6A modification increased the translational efficiency of BCL9L through the m6A reader protein YTHDF1, resulting in elevated BCL9L protein levels.

In turn, BCL9L promoted the secretion of TGF-β1, TGF-β2, and TGF-β3, creating an immunosuppressive tumor microenvironment enriched in Tregs. Through this mechanism, the mutant KRAS–METTL3–m6A–BCL9L pathway supported CRC growth and immune evasion.

Dual Targeting of KRAS and METTL3 Offers a Promising Strategy

Functional experiments confirmed the importance of BCL9L in KRAS-mutant CRC. BCL9L knockout substantially suppressed tumor growth in murine allograft models and in human CRC xenografts established in CD34⁺ humanized immune-system mice. The antitumor effect was accompanied by a marked reduction in Treg infiltration and activation of Th1-type immunity, indicating that BCL9L contributes to CRC progression partly by shaping an immunosuppressive tumor microenvironment.

The study also evaluated the therapeutic potential of simultaneously targeting mutant KRAS and METTL3. Treatment with the METTL3 inhibitors STC-15 or STM2457 enhanced the antitumor activity of mutant KRAS inhibitors and synergistically suppressed KRAS-mutant CRC growth in mouse models.

Figure 1. Co-targeting of METTL3 and mutant KRAS synergistically suppressed tumor growth. (Chen D, et al., 2026)

Collectively, these findings establish a previously unidentified connection between oncogenic KRAS signaling and m6A-mediated epitranscriptomic regulation in CRC. Mutant KRAS stabilizes METTL3 by preventing its autophagic degradation, leading to increased m6A modification and YTHDF1-dependent translation of BCL9L. Elevated BCL9L subsequently promotes TGF-β secretion and Treg accumulation, facilitating tumor progression and immune suppression.

By demonstrating that concurrent pharmacological targeting of mutant KRAS and METTL3 produces synergistic tumor suppression, this study provides a promising combination strategy for overcoming the limited response of KRAS-mutant CRC to existing targeted therapies.