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
