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ALKBH5 suppresses m6A mRNA modification of FOXM1 to drive Cetuximab resistance in KRAS-mutant colorectal cancer

Oncogene volume 44, pages 3225–3238 (2025)Cite this article

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Abstract

Colorectal cancer (CRC) is a severe health risk, and while Cetuximab is a key treatment, resistance due to KRAS mutations poses a challenge. The role of ALKBH5, often overexpressed in cancers, in KRAS-mutated CRC and its resistance to Cetuximab is not yet fully understood. This research initiates an inquiry from both cellular and animal experimental perspectives, investigating the potential of ALKBH5 to confer resistance to Cetuximab in colorectal cancer cells harboring KRAS mutations. We investigated ALKBH5 expression in clinical samples of CRC with varying responses to Cetuximab and KRAS statuses. Drug-resistant cell lines were developed using incremental drug concentrations, and the effects of ALKBH5 modulation on cell viability and proliferation were assessed using CCK-8 and clonogenic assays. The in vivo impact of ALKBH5 on drug resistance in KRAS-mutant cells was explored. Transcriptome sequencing of ALKBH5 knockdown cells pinpointed genes linked to Cetuximab resistance. We also examined ALKBH5’s regulation of FOXM1 m6A methylation with dual-luciferase and MeRIP assays and conducted FOXM1 functional reversal studies, alongside Western blot analysis of Wnt/β-catenin pathway proteins. Elevated ALKBH5 expression is positively correlated with Cetuximab resistance in KRAS-mutant CRC. ALKBH5 confers Cetuximab resistance to CRC cells in a KRAS-mutation-dependent manner in vitro and in vivo. ALKBH5 regulates FOXM1 expression through m6A demethylation, and FOXM1 can reverse Cetuximab resistance in ALKBH5-modulated KRAS-mutated CRC cells. Additionally, FOXM1 influences the sensitivity of KRAS-mutant tumors to Cetuximab by regulating the Wnt/β-catenin pathway. ALKBH5 plays a crucial role in the resistance of KRAS-mutant CRC to Cetuximab by inhibiting the m6A RNA methylation of FOXM1 and suppressing the activation of the Wnt/β-catenin signaling pathway.

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Fig. 1: Elevated ALKBH5 expression is positively correlated with Cetuximab resistance in patients with KRAS-mutant CRC.
Fig. 2: ALKBH5 confers Cetuximab resistance to CRC cells in a KRAS-mutation-dependent manner in vitro.
Fig. 3: ALKBH5 contributes to the Cetuximab resistance of KRAS-mutant CRC cells in vivo.
Fig. 4: ALKBH5 modulating FOXM1 expression through m6A demethylation in KRAS-mutated Cetux-resistant CRC cells.
Fig. 5: FOXM1 reverses Cetuximab resistance in ALKBH5-modulated KRAS-mutated CRC cells.
Fig. 6: Final validation of FOXM1’s impact on ALKBH5-regulated sensitivity to Cetuximab in KRAS-nutated tumors in vivo.

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Data availability

All data generated or used during the study appear in the submitted article.

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Funding

This work was supported by the Hospital-Level Doctoral Fund Project (grant number BS202206).

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Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang Province, China

    Hu Han, Zhiyi Lin, Xiaoping Ma, Cengceng Lu & Rongyan Ma

  2. Medical Department, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang Province, China

    Yan Li & Rui Han

  3. Department of Interventional Diagnosis and Treatment, Affiliated Cancer Hospital, Xinjiang Medical University, Urumqi, Xinjiang Province, China

    Wukui Huang

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  1. Hu Han
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Contributions

HH designed the study. HH, YL, ZL, XM, WH, CL, RM, and RH performed the research and analyzed the data. HH, Y,L and ZL contributed new methods and wrote the paper.

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Correspondence to Hu Han.

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The authors declare no competing interests.

Ethics approval and consent to participate

The research protocol was also reviewed and granted approval by the Institutional Ethics Committee of the First Affiliated Hospital of Shihezi University. Written informed consent was secured from every participant prior to their inclusion in the study. The study was executed with the utmost rigor, adhering to the ethical guidelines for animal care, and experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the First Affiliated Hospital of Shihezi University.

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Han, H., Li, Y., Lin, Z. et al. ALKBH5 suppresses m6A mRNA modification of FOXM1 to drive Cetuximab resistance in KRAS-mutant colorectal cancer. Oncogene 44, 3225–3238 (2025). https://doi.org/10.1038/s41388-025-03490-1

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