Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma
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. W...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38552-z |
| _version_ | 1797822784549683200 |
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| author | Danielle S. Potter Ruochen Du Stephan R. Bohl Kin-Hoe Chow Keith L. Ligon Raphael Bueno Anthony Letai |
| author_facet | Danielle S. Potter Ruochen Du Stephan R. Bohl Kin-Hoe Chow Keith L. Ligon Raphael Bueno Anthony Letai |
| author_sort | Danielle S. Potter |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T10:13:15Z |
| format | Article |
| id | doaj.art-1d17f8fe98d348939d13271ba1919296 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T10:13:15Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-1d17f8fe98d348939d13271ba19192962023-05-21T11:20:33ZengNature PortfolioNature Communications2041-17232023-05-0114111510.1038/s41467-023-38552-zDynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesotheliomaDanielle S. Potter0Ruochen Du1Stephan R. Bohl2Kin-Hoe Chow3Keith L. Ligon4Raphael Bueno5Anthony Letai6Department of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Oncologic Pathology, Dana-Farber Cancer InstituteHarvard Medical SchoolHarvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer InstituteAbstract 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.https://doi.org/10.1038/s41467-023-38552-z |
| spellingShingle | Danielle S. Potter Ruochen Du Stephan R. Bohl Kin-Hoe Chow Keith L. Ligon Raphael Bueno Anthony Letai Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma Nature Communications |
| title | Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma |
| title_full | Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma |
| title_fullStr | Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma |
| title_full_unstemmed | Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma |
| title_short | Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma |
| title_sort | dynamic bh3 profiling identifies pro apoptotic drug combinations for the treatment of malignant pleural mesothelioma |
| url | https://doi.org/10.1038/s41467-023-38552-z |
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