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Title: BCL-XL is an actionable target for treatment of malignant pleural mesothelioma.
Austin Authors: 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 S ;Lee, Erinna F;John, Thomas ;Fairlie, Walter Douglas 
Affiliation: Department of Mathematics and Statistics, La Trobe University, Bundoora, VIC, Australia
Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia
Medical Oncology
Issue Date: 31-Oct-2020
Date: 2020-10-31
Publication information: Cell Death Discovery 2020; 6(1): 114
Abstract: 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.
DOI: 10.1038/s41420-020-00348-1
ORCID: 0000-0002-2672-6331
Journal: Cell Death Discovery
PubMed URL: 33298868
ISSN: 2058-7716
Type: Journal Article
Appears in Collections:Journal articles

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