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

// Alan Van Goethem 1, 2 , Nurten Yigit 1, 2 , Myrthala Moreno-Smith 3 , Sanjeev A. Vasudevan 3 , Eveline Barbieri 3 , Frank Speleman 1, 2 , Jason Shohet 3 , Jo Vandesompele 1, 2, 4 and Tom Van Maerken 1, 2 1 Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium 2 Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium 3 Department of Pediatrics, Section of Hematology-Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas, USA 4 Bioinformatics Institute Ghent (BIG), Ghent University, Ghent, Belgium Correspondence to: Tom Van Maerken, email: Tom.VanMaerken@UGent.be 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.