BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
AuthorArulananda, S; O'Brien, M; Evangelista, M; Harris, TJ; Steinohrt, NS; Jenkins, LJ; Walkiewicz, M; O'Donoghue, RJJ; Poh, AR; Thapa, B; ...
Source TitleCell Death Discovery
University of Melbourne Author/sMariadason, John; Williams, David; Leong, Trishe; O'Donoghue, Robert; Poh, Ashleigh; THAPA, BIBHUSAL; CEBON, JONATHAN; LEE, ERINNA; John, Thomas
AffiliationSir Peter MacCallum Department of Oncology
Medical Biology (W.E.H.I.)
Anatomy and Neuroscience
Biochemistry and Pharmacology
Medicine (Austin & Northern Health)
Document TypeJournal Article
CitationsArulananda, S., O'Brien, M., Evangelista, M., Harris, T. J., Steinohrt, N. S., Jenkins, L. J., Walkiewicz, M., O'Donoghue, R. J. J., Poh, A. R., Thapa, B., Williams, D. S., Leong, T., Mariadason, J. M., Li, X., Cebon, J., Lee, E. F., John, T. & Douglas Fairlie, W. (2020). BCL-XL is an actionable target for treatment of malignant pleural mesothelioma. CELL DEATH DISCOVERY, 6 (1), https://doi.org/10.1038/s41420-020-00348-1.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603509
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.
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Publisher licenceCC BY
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