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VPS33A Promotes Pemigatinib Resistance in Cholangiocarcinoma via Autophagy

Mengyu Chen1,2, Man Luo3,2, Bolin Zhang4,2

  • 1Department of Thoracic Oncology, Jiangxi Cancer Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.

Digestive Diseases and Sciences
|February 20, 2026
PubMed
Abstract

Insights

VPS33A-mediated autophagy drives Pemigatinib resistance in cholangiocarcinoma (CCA). Targeting VPS33A and ULK1 may overcome drug resistance, offering new therapeutic strategies for CCA patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Pemigatinib is the first FDA-approved targeted therapy for cholangiocarcinoma (CCA).
  • Acquired resistance to Pemigatinib is a significant clinical challenge in CCA treatment.
  • Understanding resistance mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of VPS33A in mediating Pemigatinib resistance in CCA.
  • To explore the involvement of autophagy in VPS33A-driven drug resistance.
  • To identify potential therapeutic targets for overcoming Pemigatinib resistance.

Main Methods:

  • Established Pemigatinib-resistant CCA cell lines (RBE-R, HuCCT1-R).
  • Assessed cell viability, proliferation, and autophagic flux.
  • Utilized VPS33A knockdown and ULK1 overexpression for functional validation.
  • Confirmed VPS33A and ULK1 interaction via correlation analysis.

Main Results:

  • Resistant cells showed elevated VPS33A expression and autophagy-dependent resistance.
  • VPS33A knockdown suppressed autophagy, reduced ULK1 levels, and sensitized cells to Pemigatinib.
  • ULK1 overexpression restored autophagy and reversed the drug sensitivity induced by VPS33A depletion.

Conclusions:

  • VPS33A-mediated autophagy, via ULK1, sustains Pemigatinib resistance in CCA.
  • VPS33A represents a potential therapeutic target to overcome Pemigatinib resistance.
  • This study reveals a novel vulnerability in CCA treatment strategies.
Keywords:
AutophagyCholangiocarcinomaPemigatinib resistanceULK1VPS33A

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