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Lookup NU author(s): Arman Esfandiari, Dr Sirintra Nakjang, Professor John LunecORCiD
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Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 +/- a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53(Ser15) phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non-growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI(50)). Potentiation also correlated with significant increase in MDM2 inhibitor-induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53(Ser15), known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53(Ser15) and its potential use as a biomarker for response to this combination regimen. (C) 2016 AACR.
Author(s): Esfandiari A, Hawthorne TA, Nakjang S, Lunec J
Publication type: Article
Publication status: Published
Journal: Molecular Cancer Therapeutics
Year: 2016
Volume: 15
Issue: 3
Pages: 379-391
Print publication date: 01/03/2016
Online publication date: 01/02/2016
Acceptance date: 23/12/2015
ISSN (print): 1535-7163
ISSN (electronic): 1538-8514
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/1535-7163.MCT-15-0651
DOI: 10.1158/1535-7163.MCT-15-0651
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