2. Academic Validation
  3. Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma

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

  • Nat Commun. 2023 May 20;14(1):2897. doi: 10.1038/s41467-023-38552-z.
Danielle S Potter 1 2,  Ruochen Du 1 2,  Stephan R Bohl 1 2,  Kin-Hoe Chow 3 4,  Keith L Ligon 2 3 4 5 6,  Raphael Bueno 2 7,  Anthony Letai 8 9
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 2 Harvard Medical School, Boston, MA, 02215, USA.
  • 3 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 4 Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 5 Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02215, USA.
  • 6 Cancer Biology Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
  • 7 Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. Anthony_Letai@dfci.harvard.edu.
  • 9 Harvard Medical School, Boston, MA, 02215, USA. Anthony_Letai@dfci.harvard.edu.
PMID: 37210412 DOI: 10.1038/s41467-023-38552-z
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.

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