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

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 and enhanced chemosensitivity without toxicity in PDX models. Our findings suggest that targeting the mitochondria via MCL-1 enhances the efficacy of chemotherapy but co-targeting two proteins in the Bcl-2 pathways results in synergistic lethality. These results will help define a safe clinical strategy to utilize Bcl-2-targeted therapy to undermine therapeutic resistance in patients with diffuse mesothelioma.