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<p>Osimertinib resistance poses a significant clinical challenge in treating non-small cell lung carcinoma (NSCLC) patients harboring EGFR-activating or T790M mutations, highlighting the urgent need to elucidate the underlying molecular mechanisms. In this study, we show that elevated USP20 expression drives osimertinib resistance and is associated with poor clinical outcomes in osimertinib-resistant NSCLC. Mechanistically, USP20 specifically interacts with PGAM1 and catalyzes the removal of K225-linked ubiquitin chains through its C154 catalytic site, thereby stabilizing PGAM1 to enhance glycolysis and promote osimertinib resistance. Importantly, through extensive virtual drug screening, we identified compound 89131-02-2 as a novel and selective inhibitor that targets the USP20 C154 catalytic site. Pharmacological inhibition of USP20 by 89131-02-2 effectively suppressed glycolysis and restored osimertinib sensitivity in functional assays. Our findings not only establish the USP20-PGAM1 axis as a key mediator of osimertinib response but also offer a potential therapeutic strategy to overcome resistance in NSCLC patients.</p>

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USP20-mediated PGAM1 stabilization promotes glycolysis and confers osimertinib resistance in non-small cell lung carcinoma

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Yunchong Meng,
  • Xiaojun Wang,
  • Shihao Wu,
  • Wei Lin,
  • Mingliang Wang,
  • Kuo Li,
  • Peiyuan Mei,
  • Quanfu Huang,
  • Liao Yongde,
  • Na Wang

摘要

Osimertinib resistance poses a significant clinical challenge in treating non-small cell lung carcinoma (NSCLC) patients harboring EGFR-activating or T790M mutations, highlighting the urgent need to elucidate the underlying molecular mechanisms. In this study, we show that elevated USP20 expression drives osimertinib resistance and is associated with poor clinical outcomes in osimertinib-resistant NSCLC. Mechanistically, USP20 specifically interacts with PGAM1 and catalyzes the removal of K225-linked ubiquitin chains through its C154 catalytic site, thereby stabilizing PGAM1 to enhance glycolysis and promote osimertinib resistance. Importantly, through extensive virtual drug screening, we identified compound 89131-02-2 as a novel and selective inhibitor that targets the USP20 C154 catalytic site. Pharmacological inhibition of USP20 by 89131-02-2 effectively suppressed glycolysis and restored osimertinib sensitivity in functional assays. Our findings not only establish the USP20-PGAM1 axis as a key mediator of osimertinib response but also offer a potential therapeutic strategy to overcome resistance in NSCLC patients.