Journal article

A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma

Surein Arulananda, Megan O'Brien, Marco Evangelista, Laura J Jenkins, Ashleigh R Poh, Marzena Walkiewicz, Trishe Leong, John M Mariadason, Jonathan Cebon, Srividya B Balachander, Justin R Cidado, Erinna F Lee, Thomas John, Walter D Fairlie

Cell Death Discovery | SPRINGERNATURE | Published : 2021

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nano..

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University of Melbourne Researchers

Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by Tour de Cure Pioneering Grant


Awarded by NHMRC Senior Research Fellowship


Awarded by Peter Doherty Early Career Fellowship


Awarded by Australian Research Council


Awarded by Victorian Cancer Agency (Mid-Career Fellowship)


Funding Acknowledgements

Support for this work was provided by the National Health and Medical Research Council (NHMRC) of Australia Project Grant (GNT1157551) and Tour de Cure Pioneering Grant (RSP-202-18/19) to W.D.F. and T.J, NHMRC Senior Research Fellowship (GNT1046092) to J.M.M. and Peter Doherty Early Career Fellowship (GNT1166447) to A.R.P. S.A. and L.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.