BCL-XL is an actionable target for treatment of malignant pleural mesothelioma

Surein Arulananda, Megan O’Brien, Marco Evangelista, Tiffany J. Harris, Nikita S. Steinohrt, Laura J. Jenkins, Marzena Walkiewicz, Robert J.J. O’Donoghue, Ashleigh R. Poh, Bibhusal Thapa, David S. Williams, Trishe Leong, John M. Mariadason, Xia Li, Jonathan Cebon, Erinna F. Lee, Thomas John, W. Douglas Fairlie

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number114
JournalCell Death Discovery
Volume6
Issue number1
DOIs
Publication statusPublished - 1 Dec 2020
Externally publishedYes

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