Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.

A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma / Barbieri, E; De Preter, K; Capasso, Mario; Johansson, P; Man, Tk; Chen, Z; Stowers, P; Tonini, Gp; Speleman, F; Shohet, J. M.. - In: PLOS ONE. - ISSN 1932-6203. - 19:(2014), pp. 8-11. [10.1371/j.p.0079843]

A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma.

CAPASSO, Mario;
2014

Abstract

Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.
2014
A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma / Barbieri, E; De Preter, K; Capasso, Mario; Johansson, P; Man, Tk; Chen, Z; Stowers, P; Tonini, Gp; Speleman, F; Shohet, J. M.. - In: PLOS ONE. - ISSN 1932-6203. - 19:(2014), pp. 8-11. [10.1371/j.p.0079843]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/574822
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