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BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
journal contributionposted on 09.12.2020, 22:56 by Surein Arulananda, M O’Brien, M Evangelista, TJ Harris, NS Steinohrt, Laura Jenkins, M Walkiewicz, RJJ O’Donoghue, Ashleigh Poh, B Thapa, David Williams, T Leong, John Mariadason, Xia Li, Jonathan Cebon, Erinna Lee, Thomas John, Walter Fairlie
© 2020, The Author(s). 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.