Oncotarget

Research Papers:

Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma

Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A. Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele and Tom Van Maerken _

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Oncotarget. 2017; 8:57047-57057. https://doi.org/10.18632/oncotarget.18982

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Abstract

Alan Van Goethem1,2, Nurten Yigit1,2, Myrthala Moreno-Smith3, Sanjeev A. Vasudevan3, Eveline Barbieri3, Frank Speleman1,2, Jason Shohet3, Jo Vandesompele1,2,4 and Tom Van Maerken1,2

1Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium

2Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium

3Department of Pediatrics, Section of Hematology-Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas, USA

4Bioinformatics Institute Ghent (BIG), Ghent University, Ghent, Belgium

Correspondence to:

Tom Van Maerken, email: [email protected]

Keywords: neuroblastoma, idasanutlin, p53, venetoclax, synergism

Received: January 13, 2017     Accepted: June 17, 2017     Published: July 04, 2017

ABSTRACT

Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.


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