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.
Highlights
Neuroblastoma, the second most common solid tumor in childhood, is characterized by a heterogeneous clinical behavior, ranging from spontaneous regression to aggressive and inexorable disease [1]
We evaluated combination treatment of idasanutlin with 15 other targeted drugs, selected on their ability to target pathways that are considered important in neuroblastoma biology (Supplementary Table 1 provides a detailed overview of used compounds and concentration ranges)
In all three cell lines with wild-type TP53, we found that the combination of the BCL2/BCL-XL antagonist ABT-263 with idasanutlin consistently resulted in highly synergistic combination index (CI) values: 0.29, 0.27 and 0.25 for NGP, IMR-32 and SHSY5Y, respectively
Summary
Neuroblastoma, the second most common solid tumor in childhood, is characterized by a heterogeneous clinical behavior, ranging from spontaneous regression to aggressive and inexorable disease [1]. Mutations in the TP53 tumor suppressor gene are rarely encountered in primary neuroblastoma tumors (< 2%), and remain rather uncommon at relapse (< 15%) [3, 4]. Amplification and increased expression of MDM2 and suppression of CDKN2A (p14ARF) have been reported. These abnormalities converge into the central CDKN2A/MDM2/TP53 axis resulting in increased activity of MDM2, the principal TP53 inhibitor, and subsequent impairment of normal TP53 functioning [5]. The importance of MDM2-mediated suppression of the TP53 pathway in neuroblastoma has convincingly been demonstrated in vivo using an MDM2-haploinsufficient mouse model in which tumor latency was delayed while tumor incidence and growth were remarkably reduced [6]
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