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

Details

• 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
  More +
• 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. Description provided by NIOSH
• Subjects:
  • Mesothelioma
  • Neoplasms
  • Occupational Health
  • Safety
• Keywords:
  • Cellular function; Tumors; Malignancy; Mesothelioma; Neoplasms; Molecular biology
• Source:
  Mol Cancer Ther 2025 Oct; 24(10):1640-1652
• ISSN:
  1535-7163
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Dallas Region OSHA ; Pennsylvania ; Philadelphia Region OSHA ; Texas
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  13 pdf pages
• Volume:
  24
• NIOSHTIC Number:
  nn:20071677
• Contact Point Address:
  R. Taylor Ripley, Meyer DeBakey Chair of Investigative Surgery, David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 7200 Cambridge Street, Houston, TX 77030
• Email:
  R.Taylor.Ripley@bcm.edu
• Federal Fiscal Year:
  2026
• NORA Priority Area:
  Construction ; Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20060901
• End Date:
  20260831
• Download URL:
  https://stacks.cdc.gov/view/cdc/259449/cdc_259449_DS1.pdf
• File Type:
  [PDF - 14.71 MB]
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:0a2afc7ba0c4e549abca11a0347cf187a01f0ac0ace11019a51d4e92982f93ef0fa7f4f0c655c8485046a07bc8b76528baaa62fdbf0eba3044decc6a9294ec36