Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma
- BMC Med. 2026 Jan 30;24(1):126. doi: 10.1186/s12916-026-04671-9.
- 1. Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Metabolic Diseases, College of Life Sciences, Anhui Normal University, Wuhu, Anhui, China.
- 2. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
- 3. Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
- 4. Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital, Kunming, Yunnan, China.
- 5. Department of Anesthesiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
- 6. School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan, China.
- 7. Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
- 8. University of Chinese Academy of Sciences, Beijing, China. [email protected].
- 9. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected].
- 10. University of Chinese Academy of Sciences, Beijing, China. [email protected].
- # Contributed equally.
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.