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

Details

• Alternative Title:
  Molecular Cancer Therapeutics, 2025, v. 24, no. 10: Co-Targeting BCL-xL With MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.
• Journal Article:
  Molecular Cancer Therapeutics
• Personal Author:
  Xu, Yuan ; Medina, Cristian G. ; Surman, Deborah R. ; Dobrolecki, Lacey E. ; Vilchis, Monica ; Ramineni, Maheshwari ; Hilsenbeck, Susan G. ; Li, Yanming ; Li, Naren ; Wu, Siqi ; Aggison, Jaylon C. ; Chen, Xi ; Zhu, Yi ; Shen, Ying H. ; Ripley, R. Taylor
• Description:
  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.
• Content Notes:
  Author manuscript
• Subjects:
  • Humans
  • Myeloid Cell Leukemia Sequence 1 Protein
  • bcl-X Protein
  • Mitochondria
  • Animals
  • Mice
  • Xenograft Model Antitumor Assays
  • Mesothelioma
  • Apoptosis
  • Cell Line, Tumor
• Source:
  Molecular Cancer Therapeutics, 2025, v. 24, no. 10
• DOI:
  https://doi.org/10.1158/1535-7163.MCT-24-0873
• ISSN:
  1535-7163 ; 1538-8514
• Pubmed ID:
  40804773
• Pubmed Central ID:
  PMC12475887
• Document Type:
  Text
• Funding:
  S10 OD032185/OD/NIH HHSUnited States/ ; R37 CA289419/CA/NCI NIH HHSUnited States/ ; R03 CA252685-01/National Cancer Institute (NCI)/ ; R03 CA252685/CA/NCI NIH HHSUnited States/ ; U24 OH009077/OH/NIOSH CDC HHSUnited States/ ; R21 CA256466/CA/NCI NIH HHSUnited States/ ; S10 RR024574/RR/NCRR NIH HHSUnited States/ ; R01 HL130249/HL/NHLBI NIH HHSUnited States/ ; P30 CA125123/CA/NCI NIH HHSUnited States/ ; R01 CA290173/CA/NCI NIH HHSUnited States/ ; UM1 HG006348/HG/NHGRI NIH HHSUnited States/ ; U01 CA214195/CA/NCI NIH HHSUnited States/ ; R01 DK114356/DK/NIDDK NIH HHSUnited States/
• Genre:
  Journal Article
• Pages in Document:
  1640-1652 (25 pdf pages)
• Volume:
  24
• Issue:
  10
• Download URL:
  https://stacks.cdc.gov/view/cdc/261178/cdc_261178_DS1.pdf
• File Type:
  [PDF - 2.93 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:240b0e394645553901ac0103c39254453852cc2aafd0e6f403909559748b57fc7ed12698db8620ae47e45ae3d03cdaa91fb9bdddebe9993529f1ff491c5ab6e5