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BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BC...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603509/ https://www.ncbi.nlm.nih.gov/pubmed/33298868 http://dx.doi.org/10.1038/s41420-020-00348-1 |
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author | Arulananda, Surein O’Brien, Megan Evangelista, Marco Harris, Tiffany J. Steinohrt, Nikita S. Jenkins, Laura J. Walkiewicz, Marzena O’Donoghue, Robert J. J. Poh, Ashleigh R. Thapa, Bibhusal Williams, David S. Leong, Trishe Mariadason, John M. Li, Xia Cebon, Jonathan Lee, Erinna F. John, Thomas Fairlie, W. D. |
author_facet | Arulananda, Surein O’Brien, Megan Evangelista, Marco Harris, Tiffany J. Steinohrt, Nikita S. Jenkins, Laura J. Walkiewicz, Marzena O’Donoghue, Robert J. J. Poh, Ashleigh R. Thapa, Bibhusal Williams, David S. Leong, Trishe Mariadason, John M. Li, Xia Cebon, Jonathan Lee, Erinna F. John, Thomas Fairlie, W. D. |
author_sort | Arulananda, Surein |
collection | PubMed |
description | Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM. |
format | Online Article Text |
id | pubmed-7603509 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76035092020-11-02 BCL-XL is an actionable target for treatment of malignant pleural mesothelioma Arulananda, Surein O’Brien, Megan Evangelista, Marco Harris, Tiffany J. Steinohrt, Nikita S. Jenkins, Laura J. Walkiewicz, Marzena O’Donoghue, Robert J. J. Poh, Ashleigh R. Thapa, Bibhusal Williams, David S. Leong, Trishe Mariadason, John M. Li, Xia Cebon, Jonathan Lee, Erinna F. John, Thomas Fairlie, W. D. Cell Death Discov Article Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM. Nature Publishing Group UK 2020-10-31 /pmc/articles/PMC7603509/ /pubmed/33298868 http://dx.doi.org/10.1038/s41420-020-00348-1 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Arulananda, Surein O’Brien, Megan Evangelista, Marco Harris, Tiffany J. Steinohrt, Nikita S. Jenkins, Laura J. Walkiewicz, Marzena O’Donoghue, Robert J. J. Poh, Ashleigh R. Thapa, Bibhusal Williams, David S. Leong, Trishe Mariadason, John M. Li, Xia Cebon, Jonathan Lee, Erinna F. John, Thomas Fairlie, W. D. BCL-XL is an actionable target for treatment of malignant pleural mesothelioma |
title | BCL-XL is an actionable target for treatment of malignant pleural mesothelioma |
title_full | BCL-XL is an actionable target for treatment of malignant pleural mesothelioma |
title_fullStr | BCL-XL is an actionable target for treatment of malignant pleural mesothelioma |
title_full_unstemmed | BCL-XL is an actionable target for treatment of malignant pleural mesothelioma |
title_short | BCL-XL is an actionable target for treatment of malignant pleural mesothelioma |
title_sort | bcl-xl is an actionable target for treatment of malignant pleural mesothelioma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603509/ https://www.ncbi.nlm.nih.gov/pubmed/33298868 http://dx.doi.org/10.1038/s41420-020-00348-1 |
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