ArticleBMC medicine2026
Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma.
Article in BMC medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Post-translational modifications of integrins: molecular mechanisms and pathological implications.Cellular and molecular life sciences : CMLS · 2026Review
- From Platelet Toxicity to Precision Targeting: Evolving Strategies to Overcome Thrombocytopenia in BCL-2/BCL-XL Inhibition.Health science reports · 2026Article
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Authors and funding
14 authors.
Funding
Abstract
backgroundCholangiocarcinoma (CCA) remains a highly lethal malignancy with a dismal prognosis, primarily driven by therapeutic resistance. A dominant resistance mechanism involves overexpression of anti-apoptotic BCL-2 proteins (BCL-XL, BCL-2, MCL-1). While direct inhibition of these proteins shows efficacy, its clinical utility is frequently limited by dose-dependent hematotoxicity-as exemplified by ABT263, a BCL-XL/BCL-2 dual inhibitor that induces severe thrombocytopenia.
methodsWe performed integrated analyses of BCL-2 family mRNA/protein expression in clinical CCA specimens and preclinical cell lines. Leveraging proteolysis-targeting chimera (PROTAC) technology, we investigated the therapeutic application of BCL-XL-specific degraders, both as monotherapy and in combination with gemcitabine, to selectively target CCA cells while minimizing hematologic toxicity.
resultsIntegrated clinical-experimental data identified BCL-XL as a principal determinant of therapeutic sensitivity in CCA. In vitro, the cereblon (CRBN)-based PROTAC XZ739 demonstrated superior efficacy to its von Hippel-Lindau tumor suppressor (VHL)-based counterpart DT2216, reducing CCA cell viability via apoptosis induction. In vivo, XZ739 synergized with gemcitabine to suppress tumor growth in a CCA xenograft model, achieving robust efficacy without significant thrombocytopenia-a critical advance over conventional BCL-XL inhibitors.
conclusionsThese findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.
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