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

journal contribution
posted on 09.12.2020, 22:56 by Surein Arulananda, M O’Brien, M Evangelista, TJ Harris, NS Steinohrt, Laura JenkinsLaura Jenkins, M Walkiewicz, RJJ O’Donoghue, Ashleigh PohAshleigh Poh, B Thapa, David WilliamsDavid Williams, T Leong, John MariadasonJohn Mariadason, Xia LiXia Li, Jonathan CebonJonathan Cebon, Erinna LeeErinna Lee, Thomas John, Walter FairlieWalter 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.

Funding

Support for this work was provided by the National Health and Medical Research Council of Australia Project Grant (GNT1157551) and Tour de Cure Pioneering Grant (RSP-202-18/19) to W.D.F. and T.J., Senior Research Fellowship (GNT1046092) to J.M.M. and Peter Doherty Early Career Fellowship (GNT1166447) to A.R.P. S.A. and L.J.J. are the recipients of a La Trobe University Post Graduate Research Scholarship and S.A. a Lung Foundation Australia Grant-in-Aid. E.F.L. is a recipient of fellowships from the Australian Research Council (Future Fellowship FT150100212) and the Victorian Cancer Agency (Mid-Career Fellowship MCRF19045). We thank Mr. Josh Lorimer and Ms. Haley Sleep from the Austin Health Bio Resources Facility for providing technical mouse work support. We are grateful to Mr. David Baloyan for his technical expertise with FACS-based assays and sorting.

History

Publication Date

31/10/2020

Journal

Cell Death Discovery

Volume

6

Issue

1

Article Number

114

Pagination

11p.

Publisher

Springer Nature

ISSN

2058-7716

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.