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

doi:10.1038/s41420-020-00348-1

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

Olivia Newton-John Cancer Research Institute
Austin Health
University of Melbourne
La Trobe University
Peter Maccallum Cancer Centre

Research output: Contribution to journal › Article › peer-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 language	English
Article number	114
Journal	Cell Death Discovery
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s41420-020-00348-1
Publication status	Published - 1 Dec 2020
Externally published	Yes

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SDG 3 Good Health and Well-being

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Arulananda, S., O’Brien, M., Evangelista, M., Harris, T. J., Steinohrt, N. S., Jenkins, L. J., Walkiewicz, M., O’Donoghue, R. J. J., Poh, A. R., Thapa, B., Williams, D. S., Leong, T., Mariadason, J. M., Li, X., Cebon, J., Lee, E. F., John, T., & Douglas Fairlie, W. (2020). BCL-XL is an actionable target for treatment of malignant pleural mesothelioma. Cell Death Discovery, 6(1), Article 114. https://doi.org/10.1038/s41420-020-00348-1

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title = "BCL-XL is an actionable target for treatment of malignant pleural mesothelioma",

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.",

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

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Arulananda, S, O’Brien, M, Evangelista, M, Harris, TJ, Steinohrt, NS, Jenkins, LJ, Walkiewicz, M, O’Donoghue, RJJ, Poh, AR, Thapa, B, Williams, DS, Leong, T, Mariadason, JM, Li, X, Cebon, J, Lee, EF, John, T & Douglas Fairlie, W 2020, 'BCL-XL is an actionable target for treatment of malignant pleural mesothelioma', Cell Death Discovery, vol. 6, no. 1, 114. https://doi.org/10.1038/s41420-020-00348-1

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.

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

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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 -

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

Abstract

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