The KDM3A/METTL16/PDK1 axis: A novel prognostic biomarker and therapeutic target for TKI-resistant lung cancer

Lung cancer is the leading cause of cancer-related deaths globally, and for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), targeted epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and osimertinib are standard first-line therapies. However, the inevitable emergence of acquired drug resistance severely limits long-term patient survival. While metabolic reprogramming and aerobic glycolysis are known hallmarks of tumor progression, the specific epigenetic pathways fueling TKI resistance remain elusive.

This new research, published in Genes & Diseases journal by a team from Zhengzhou University, Southeast University, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, Chongqing University School of Medicine and Bioinformatics Institute, A∗STAR, investigated a novel multi-layered epigenetic network—the KDM3A/METTL16/PDK1 signaling axis—to uncover its critical role in lung cancer TKI resistance and tumorigenesis.

Through extensive bioinformatic and clinical cohort analyses, the researchers established that pyruvate dehydrogenase kinase 1 (PDK1), a key gatekeeper of glycolysis, is significantly overexpressed in TKI-resistant lung cancer cells and human tumor tissues, tightly correlating with poor overall survival. Mechanistic in vitro studies revealed a fascinating dual-regulation system driving this PDK1 elevation. Transcriptionally, the histone demethylase KDM3A removes suppressive H3K9me1 and H3K9me2 marks at the PDK1 promoter, directly accelerating PDK1 gene transcription.

Simultaneously, KDM3A drives a post-transcriptional mechanism by upregulating the RNA m6A methyltransferase METTL16. METTL16 subsequently facilitates the m6A modification of PDK1 mRNA, which is then recognized by the reader protein IGF2BP1, fundamentally enhancing the mRNA stability of PDK1. This combined epigenetic surge of PDK1 forces the tumor cells to aggressively upregulate glycolytic metabolism, promoting robust cell proliferation, migration, and profound resistance to both gefitinib and osimertinib.

Remarkably, the study demonstrated that this resistant phenotype could be successfully reversed. In vitro assays proved that silencing KDM3A, METTL16, or PDK1 profoundly sensitized resistant cells to gefitinib and triggered widespread apoptosis. Moving to in vivo mouse xenograft models, the researchers confirmed that utilizing the selective small-molecule PDK1 inhibitor JX06 alongside gefitinib yielded a powerful synergistic anti-tumor effect. This dual-treatment severely impaired tumor growth, triggered mitochondrial depolarization to induce early apoptosis, and significantly reduced tumor angiogenesis compared to monotherapy.

While these comprehensive data robustly highlight the critical influence of the KDM3A/METTL16/PDK1 axis in driving metabolic and epigenetic TKI evasion, additional clinical trials are necessary to fully integrate these targeted interventions.

In conclusion, deciphering and simultaneously targeting this intricate epigenetic-metabolic signaling network offers a powerful new strategy to overcome acquired drug resistance. This profound finding positions specific PDK1 inhibitors combined with EGFR-TKIs as compelling therapeutic candidates for the next generation of precision lung cancer treatments.

Reference
Title of Original Paper: PDK1 elevation was induced by epigenetic modifications of KDM3A and METTL16 to mediate TKI resistance and cancer development

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101947

Funding Information:
The National Natural Science Foundation of China (No. 82073393)
Research and Development Plan of Science and Technology in Henan Province, China (No. 232301420060)
Natural Science Foundation of Henan, China (No. 242300421086)
The Science and Technology Research Project of Henan Province, China (No. SBGJ202302023)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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(A) The PC-9 and PC-9/G cells were treated with various concentrations of gefitinib for 72 h, and cell viabilities were detected by CCK-8 assay. (B) PC-9/G cells induced higher glucose consumption and lactate production rates compared with PC-9 cells. (C) The mRNA and protein expression levels of PDK1 were tested by quantitative reverse transcription PCR and Western blotting in PC-9 and PC-9/G cell lines. (D) The protein expression levels of PDK1 were tested by Western blotting in PC-9, PC-9/OR, HCC827, and HCC827/OR cell lines. (E) Indicated cells were treated with gefitinib of different concentrations for 72 h, and PDK1 knockdown in PC-9/G cells rendered cells more sensitive to gefitinib, while forced expression of PDK1 in PC-9 cells made cells more resistant to gefitinib. (F) The apoptosis rates were determined by flow cytometry, and PDK1 knockdown in PC-9/G cells induced higher apoptosis rates. Data were statistically analyzed with Student’s t-test, and values were shown as mean ± standard deviation. ∗P < 0.05 and ∗∗P < 0.01.
(A) The analysis results of gene correlation analysis from the LUNG CANCER EXPLORER database showed that KDM3A was positively correlated with PDK1. (B) The Starbase database also confirmed that there was a positive correlation between KDM3A and PDK1. (C) The mRNA and protein expression levels of KDM3A were tested by quantitative reverse transcription PCR and Western blotting in PC-9 and PC-9/G cells. (D) The protein expression levels of KDM3A were tested by Western blotting in PC-9, PC-9/OR, HCC827, and HCC827/OR cell lines. (E) After silencing KDM3A in PC-9/G cells, the sensitivity of the cells to gefitinib increased. (F) The apoptosis rates were determined by flow cytometry, and KDM3A knockdown in PC-9/G cells induced higher apoptosis rates. (G) KDM3A knockdown in PC-9/G cells reduced the expression levels of PDK1, while the expression levels of H3K9me1 and H3K9me2 were increased. (H) The ENCODE database showed there were binding peaks of H3K9me1, H3K9me2, and KDM3A at the promoter region of PDK1. (I) Chromatin immunoprecipitation assay was conducted to determine the binding sites of KDM3A at the promoter region of the PDK1 gene. Cross-linked and sheared chromatin was immunoprecipitated with anti-KDM3A/histone H3 antibody or IgG, and quantitative reverse transcription PCR was used to detect the enrichment percentages. Data were statistically analyzed with Student’s t-test, and values were shown as mean ± standard deviation. ∗P < 0.05 and ∗∗P < 0.01.
The PC-9/G cells (5 × 106 cells) were inoculated subcutaneously on the back of nude mice. When the tumor reached approximately 5 × 5 mm2, the nude mice were randomly divided into four groups (n = 5 per group) and treated with saline, gefitinib (25 mg/kg), JX06 (30 mg/kg), or gefitinib (25 mg/kg) plus JX06 (30 mg/kg). (A–C) Tumor volumes and weights were analyzed, and dual-treatment of JX06 and gefitinib significantly inhibited tumor volumes and tumor weights. (D) Animal weights between the four groups did not show any significant difference. (E) Representative images of immunohistochemical staining of Ki67 and CD31 in paraffin-embedded xenograft tumor tissues, and the expression levels of Ki67 and CD31 were quantified for six microscopic fields of the tumor samples. Data were statistically analyzed with Student’s t-test, and values were shown as mean ± standard deviation. ∗P < 0.05 and ∗∗P < 0.01.

08/06/2026 Compuscript Ltd

Regions: Europe, Ireland

Keywords: Science, Life Sciences

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