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Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma

Author

Listed:
  • Danielle S. Potter

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Ruochen Du

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Stephan R. Bohl

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Kin-Hoe Chow

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Keith L. Ligon

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Brigham and Women’s Hospital)

  • Raphael Bueno

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Anthony Letai

    (Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.

Suggested Citation

  • Danielle S. Potter & Ruochen Du & Stephan R. Bohl & Kin-Hoe Chow & Keith L. Ligon & Raphael Bueno & Anthony Letai, 2023. "Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38552-z
    DOI: 10.1038/s41467-023-38552-z
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    References listed on IDEAS

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    1. Valerie A. Fadok & Donna L. Bratton & David M. Rose & Alan Pearson & R. Alan B. Ezekewitz & Peter M. Henson, 2000. "A receptor for phosphatidylserine-specific clearance of apoptotic cells," Nature, Nature, vol. 405(6782), pages 85-90, May.
    2. Camilo Guzmán & Manish Bagga & Amanpreet Kaur & Jukka Westermarck & Daniel Abankwa, 2014. "ColonyArea: An ImageJ Plugin to Automatically Quantify Colony Formation in Clonogenic Assays," PLOS ONE, Public Library of Science, vol. 9(3), pages 1-9, March.
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