{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zeng Q"],"funding":["CAS &quot;Light of West China&quot;","Yunnan Fundamental Research Projects","National Key R&amp;D Program of China","the Outstanding Innovative Research Team for Molecular Enzymology and Detection in Anhui Provincial Universities","National Key R&D Program of China","Technology Talent and Platform Plan of Yunnan Province","CAS \"Light of West China\"","National Natural Science Foundation of China","Academician Expert Workstation of Yunnan Kunming"],"pagination":["126"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12930748"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["24(1)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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."],"journal":["BMC medicine"],"pubmed_title":["Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma."],"pmcid":["PMC12930748"],"funding_grant_id":["82171558","2023YFC3603300","22277131","YSZJGZZ-2022063","202305AF150160","202305AH340006","xbzg-zdsys-202312","2022AH010012"],"pubmed_authors":["Yang J","Zeng Q","Pan Y","Dong X","Zhu G","Liu X","Lai X","Luo Q","Yang Y","He Y","Zhang Y","Zhang X","Hu L","Zhang A"],"additional_accession":[]},"is_claimable":false,"name":"Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma.","description":"<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Jan","modification":"2026-07-09T12:24:29.731Z","creation":"2026-07-09T11:17:49.502Z"},"accession":"S-EPMC12930748","cross_references":{"pubmed":["41618329"],"doi":["10.1186/s12916-026-04671-9"]}}