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  -