title: Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner.
abstract: 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 GI50). 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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Arman
authors.initials: A
authors.lastname: Esfandiari
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hawthorne
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Sirintra
authors.initials: S
authors.lastname: Nakjang
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. john.lunec@ncl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Lunec
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D000071636:Protein Phosphatase 2C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D004151:Dipeptides; C587624:GSK2830371; D007093:Imidazoles; D010879:Piperazines; D011759:Pyrrolidines; C586849:RG7388; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D062366:para-Aminobenzoates; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; C000607458:PPM1D protein, human; D000071636:Protein Phosphatase 2C; D053148:Caspase 3; D053179:Caspase 7
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