Oncotarget

Research Papers:

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 and M. Emmy M. Dolman

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Oncotarget. 2016; 7:27946-27958. https://doi.org/10.18632/oncotarget.8547

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Abstract

Laurel T. Bate-Eya1, Ilona J.M. den Hartog1, Ida van der Ploeg1, Linda Schild1, Jan Koster1, Evan E. Santo1, Ellen M. Westerhout1, Rogier Versteeg1, Huib N. Caron2, Jan J. Molenaar1, M. Emmy M. Dolman1

1Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands

2Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Correspondence to:

M. Emmy M. Dolman, e-mail: [email protected]

Keywords: neuroblastoma, ABT199, BCL-2, MCL-1, resistance

Received: November 26, 2015     Accepted: March 18, 2016     Published: April 1, 2016

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.


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