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

Yunchong Meng1, Xiaojun Wang1, Shihao Wu1

  • 1Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Oncogene
|July 8, 2026
PubMed

Insights

Elevated USP20 expression drives drug resistance in non-small cell lung cancer (NSCLC) by stabilizing PGAM1 and enhancing glycolysis. Targeting USP20 with compound 89131-02-2 can overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Osimertinib resistance is a major challenge for non-small cell lung cancer (NSCLC) patients with EGFR mutations.
  • Understanding the molecular mechanisms of resistance is crucial for developing new therapeutic strategies.

Purpose of the Study:

  • To investigate the role of USP20 in osimertinib resistance in NSCLC.
  • To identify potential therapeutic targets and agents to overcome osimertinib resistance.

Main Methods:

  • Assessed USP20 expression in osimertinib-resistant NSCLC.
  • Investigated the interaction between USP20 and PGAM1.
  • Utilized virtual drug screening to identify USP20 inhibitors.
  • Evaluated the efficacy of compound 89131-02-2 in functional assays.

Main Results:

  • Elevated USP20 expression correlates with osimertinib resistance and poor clinical outcomes in NSCLC.
  • USP20 deubiquitinates and stabilizes PGAM1, enhancing glycolysis and promoting resistance.
  • Compound 89131-02-2 selectively inhibits USP20's catalytic site.
  • Inhibition of USP20 suppressed glycolysis and restored osimertinib sensitivity.

Conclusions:

  • The USP20-PGAM1 axis is a key mediator of osimertinib resistance in NSCLC.
  • USP20 is a potential therapeutic target for overcoming osimertinib resistance.
  • Compound 89131-02-2 represents a promising strategy to re-sensitize NSCLC to osimertinib.

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