Language
English
Publication Date
8-14-2025
Journal
Molecular Cancer Therapeutics
DOI
10.1158/1535-7163.MCT-24-0873
PMID
40804773
PMCID
PMC12475887
PubMedCentral® Posted Date
9-28-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Diffuse mesothelioma (DM) 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 anti-apoptotic 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 domain (BH)-3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells (PDC), and patient-derived xenografts (PDX) by BH3 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 non-canonical 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 anti-apoptotic 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 DM.
Published Open-Access
yes
Recommended Citation
Xu, Yuan; Medina, Cristian G; Surman, Deborah R; et al., "Co-Targeting Bcl-xL with Mcl-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma" (2025). Faculty and Staff Publications. 4847.
https://digitalcommons.library.tmc.edu/baylor_docs/4847
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