TY - JOUR
T1 - BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
AU - Arulananda, Surein
AU - O’Brien, Megan
AU - Evangelista, Marco
AU - Harris, Tiffany J.
AU - Steinohrt, Nikita S.
AU - Jenkins, Laura J.
AU - Walkiewicz, Marzena
AU - O’Donoghue, Robert J.J.
AU - Poh, Ashleigh R.
AU - Thapa, Bibhusal
AU - Williams, David S.
AU - Leong, Trishe
AU - Mariadason, John M.
AU - Li, Xia
AU - Cebon, Jonathan
AU - Lee, Erinna F.
AU - John, Thomas
AU - Douglas Fairlie, W.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/85094841497
U2 - 10.1038/s41420-020-00348-1
DO - 10.1038/s41420-020-00348-1
M3 - Article
AN - SCOPUS:85094841497
SN - 2058-7716
VL - 6
JO - Cell Death Discovery
JF - Cell Death Discovery
IS - 1
M1 - 114
ER -
