VPS33A promueve la resistencia a pemigatinib en colangiocarcinoma a través de la autofagia

Pemigatinib, the inaugural FDA-approved targeted therapy for cholangiocarcinoma (CCA), represents a major advancement in the treatment of this malignancy. Nevertheless, the inevitable emergence of acquired resistance highlights an urgent need for innovative strategies to address this clinical challenge. This study investigates the role of VPS33A in modulating autophagy to mediate Pemigatinib resistance in CCA.

Pemigatinib-resistant cell lines were generated through chronic drug exposure. Cell viability and proliferation were evaluated using CCK-8 and EdU experiments. Autophagic flux was assessed using GFP-RFP-LC3 dual fluorescence imaging and transmission electron microscopy, while the interaction between VPS33A and ULK1 was confirmed through correlation analysis. Functional validation was conducted using both in vitro and in vivo experiments.

We successfully established Pemigatinib-resistant RBE-R and HuCCT1-R cell lines, which exhibited elevated VPS33A expression and autophagy-dependent drug resistance. Mechanistically, VPS33A knockdown reduced ULK1 protein levels, suppressed autophagy, and increased cellular sensitivity to Pemigatinib. In contrast, ULK1 overexpression restored autophagic activity and reversed the enhanced drug sensitivity induced by VPS33A depletion.

VPS33A-mediated autophagy sustains Pemigatinib resistance in CCA through ULK1, revealing a targetable vulnerability that could help overcome current therapeutic limitations.