Toggle Main Menu Toggle Search

Open Access padlockePrints

Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner

Lookup NU author(s): Arman Esfandiari, Dr Sirintra Nakjang, Professor John LunecORCiD


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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.

Publication metadata

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


DOI: 10.1158/1535-7163.MCT-15-0651


Altmetrics provided by Altmetric


Funder referenceFunder name
C240/A15751Cancer Research UK
C0190R4011Northern Institute for Cancer Research
C0190R4011Newcastle University