Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma

作者：Yuan Xu, Cristian G. Medina, Deborah R. Surman, Lacey Elizabeth Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan Galloway Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C. Aggison, Xi Chen, Yi Zhu, Ying H. Shen, Robert Taylor Ripley · 发表于：Molecular Cancer Therapeutics · 年份：2025 · DOI：10.1158/1535-7163.mct-24-0873 · 被引用次数：3 · 研究领域：Occupational and environmental lung diseases、Cell death mechanisms and regulation、Cancer Research and Treatments

Diffuse mesothelioma is a rare but highly aggressive and treatment-resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid cell leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are antiapoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance. We investigated whether B-cell homology domain3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells, and patient-derived xenografts (PDX) by B-cell homology domain-3 profiling; we observed striking consistency which enabled cross-model comparisons. Next, we co-targeted BCL-xl and MCL-1 and noted that the combination synergistically reduced cell viability and increased apoptosis. Mechanistically, BCL-xL inhibition affected the cells through both the canonical and the emerging noncanonical apoptotic pathways. BCL-xL induced mitochondrial depolarization which resulted in MCL-1 cellular dependency, rendering cells highly sensitive to MCL-1 inhibition. Next, we co-targeted BCL-xL and MCL-1 in vivo which induced synthetic lethality in PDX models within hours, implying that this approach is not a safe strategy for clinical development. However, targeting MCL-1, which exerts its antiapoptotic activity without non-apoptotic on-target effects, decreased the mitochondrial threshold for apoptosis a...