BMC medicine · 2026
Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma.
СтатьяНазвание и аннотация: Перевод в очереди
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Zeng Qinghua, Zhang Yan, Yang Yiwen, Liu Xin, Dong Xin, Pan Yongzhang, Hu Li, Zhang Ao, Yang Jian, Luo Qiuni, Lai Xiang, Zhu Guoping, Zhang Xuan, He Yonghan
Аннотация
BACKGROUND: Cholangiocarcinoma (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.
METHODS: We 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.
RESULTS: Integrated 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.
CONCLUSIONS: These 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.
METHODS: We 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.
RESULTS: Integrated 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.
CONCLUSIONS: These 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.