High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition

Laurel T. Bate-Eya; Ilona J. M. den Hartog; Ida van der Ploeg; Linda Schild; Jan Koster; Evan E. Santo; Ellen M. Westerhout; Rogier Versteeg; Huib N. Caron; Jan J. Molenaar; M. Emmy M. Dolman

doi:https://doi.org/10.18632/oncotarget.8547

High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition

Laurel T. Bate-Eya, Ilona J. M. den Hartog, Ida van der Ploeg, Linda Schild, Jan Koster, Evan E. Santo, Ellen M. Westerhout, Rogier Versteeg, Huib N. Caron, Jan J. Molenaar, M. Emmy M. Dolman

Research output: Contribution to journal › Article › Academic › peer-review

47 Citations (Scopus)

Abstract

The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression

Original language	English
Pages (from-to)	27946-27958
Journal	Oncotarget
Volume	7
Issue number	19
DOIs	https://doi.org/10.18632/oncotarget.8547
Publication status	Published - 2016

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Bate-Eya, L. T., den Hartog, I. J. M., van der Ploeg, I., Schild, L., Koster, J., Santo, E. E., Westerhout, E. M., Versteeg, R., Caron, H. N., Molenaar, J. J., & Dolman, M. E. M. (2016). High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. Oncotarget, 7(19), 27946-27958. https://doi.org/10.18632/oncotarget.8547

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title = "High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition",

abstract = "The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression",

author = "Bate-Eya, {Laurel T.} and {den Hartog}, {Ilona J. M.} and {van der Ploeg}, Ida and Linda Schild and Jan Koster and Santo, {Evan E.} and Westerhout, {Ellen M.} and Rogier Versteeg and Caron, {Huib N.} and Molenaar, {Jan J.} and Dolman, {M. Emmy M.}",

year = "2016",

doi = "https://doi.org/10.18632/oncotarget.8547",

language = "English",

volume = "7",

pages = "27946--27958",

journal = "Oncotarget",

issn = "1949-2553",

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Bate-Eya, LT, den Hartog, IJM, van der Ploeg, I, Schild, L, Koster, J, Santo, EE, Westerhout, EM , Versteeg, R, Caron, HN, Molenaar, JJ & Dolman, MEM 2016, 'High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition', Oncotarget, vol. 7, no. 19, pp. 27946-27958. https://doi.org/10.18632/oncotarget.8547

High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. / Bate-Eya, Laurel T.; den Hartog, Ilona J. M.; van der Ploeg, Ida et al.
In: Oncotarget, Vol. 7, No. 19, 2016, p. 27946-27958.

Research output: Contribution to journal › Article › Academic › peer-review

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AU - Bate-Eya, Laurel T.

AU - den Hartog, Ilona J. M.

AU - van der Ploeg, Ida

AU - Schild, Linda

AU - Koster, Jan

AU - Santo, Evan E.

AU - Westerhout, Ellen M.

AU - Versteeg, Rogier

AU - Caron, Huib N.

AU - Molenaar, Jan J.

AU - Dolman, M. Emmy M.

PY - 2016

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AB - The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression

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DO - https://doi.org/10.18632/oncotarget.8547

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