2. Academic Validation
  3. METTL3 contributes to osimertinib resistance in non-small cell lung cancer cell lines by regulating CDC25A and AURKB mRNA stability

METTL3 contributes to osimertinib resistance in non-small cell lung cancer cell lines by regulating CDC25A and AURKB mRNA stability

  • Cell Signal. 2025 Oct 1:136:112156. doi: 10.1016/j.cellsig.2025.112156.
Ryusuke Suzuki 1,  Minoru Terashima 2,  Akihiko Ishimura 1,  Makiko Meguro-Horike 3,  Shin-Ichi Horike 3,  Sasithorn Wanna-Udom 4,  Takahisa Takino 5,  Takeshi Suzuki 6
Affiliations

Affiliations

  • 1 Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
  • 2 Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
  • 3 Division of Integrated Omics Research, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
  • 4 Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.
  • 5 Division of Education for Global Standard, Institute of Liberal Arts and Science, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
  • 6 Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: suzuki-t@staff.kanazawa-u.ac.jp.
PMID: 41043761 DOI: 10.1016/j.cellsig.2025.112156
Abstract

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is used as a first-line therapy for non-small cell lung Cancer (NSCLC) harboring EGFR mutations. Nevertheless, the emergence of acquired drug resistance poses a significant challenge, leading to poor clinical outcomes. METTL3, a key methyltransferase responsible for N6-methyladenosine (m6A) modification of RNA, has been implicated in Cancer development and progression across various Cancer types. In this study, we explored the role of METTL3 in acquired resistance to osimertinib and assessed its potential as a therapeutic target. Using METTL3 knockdown EGFR-mutated NSCLC cell lines, we found that downregulation of METTL3 suppressed the acquisition of osimertinib resistance. Microarray analysis and qRT-PCR revealed that CDC25A and AURKB are downstream target genes of METTL3, with METTL3 facilitating the stabilization of their mRNAs. Downregulation of these METTL3 target genes also attenuated osimertinib resistance. Furthermore, we evaluated the effects of combining osimertinib with either a METTL3 Inhibitor or a CDC25A inhibitor, both of which increased drug efficacy by promoting Apoptosis. Collectively, this study highlights the involvement of METTL3 in the initial acquisition of osimertinib resistance and the therapeutic potential of targeting the METTL3-mediated regulatory pathway.

Keywords

METTL3; NSCLC; Osimertinib resistance; m6A modification.

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