TY - JOUR AU - Arulananda, S AU - O'Brien, M AU - Evangelista, M AU - Harris, TJ AU - Steinohrt, NS AU - Jenkins, LJ AU - Walkiewicz, M AU - O'Donoghue, RJJ AU - Poh, AR AU - Thapa, B AU - Williams, DS AU - Leong, T AU - Mariadason, JM AU - Li, X AU - Cebon, J AU - Lee, EF AU - John, T AU - Douglas Fairlie, W Y2 - 2020/11/26 Y1 - 2020/10/31 SN - 2058-7716 UR - http://hdl.handle.net/11343/252268 AB - 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. LA - English PB - SPRINGERNATURE T1 - BCL-XL is an actionable target for treatment of malignant pleural mesothelioma DO - 10.1038/s41420-020-00348-1 IS - Cell Death Discovery VL - 6 IS - 1 L1 - /bitstream/handle/11343/252268/s41420-020-00348-1.pdf?sequence=1&isAllowed=y ER -