Abstract
Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity.
Highlights
Inactivation of the crucial tumor suppressor, TP53, is a common event in tumorigenesis
These results indicate that elevated MDM2 expression in neuroblastomas is associated with more aggressive disease
As TP53 mutations occur in less than 2% of primary tumors [2,3,4], and only in 14% of relapse cases [5], neuroblastoma is expected to be especially susceptible to MDM2 inhibitors
Summary
Inactivation of the crucial tumor suppressor, TP53, is a common event in tumorigenesis. TP53 activity can be functionally inhibited by TP53 mutation or deregulating components of the TP53 pathway. MDM2-TP53 binding is known to inhibit TP53 transcriptional activity [6]. MDM2 itself is a transcriptional TP53 target, indicating the presence of a negative autoregulatory feedback loop between MDM2 and TP53 [8]. In a study of 41 primary tumors, 36.6% harbored either an MDM2 amplification or a mutational or epigenetic inactivation of CDKN2A, a negative regulator of MDM2 [5]. MYCN amplification occurs in approximately 45% of primary high-risk neuroblastomas and is the strongest independent negative prognostic risk factor in patients [9]. Despite the low mutation rate of TP53 in neuroblastoma, the TP53-MDM2 axis appears to be deregulated in at least a subgroup of high-risk neuroblastomas, identifying it as an actionable target
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