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Ref Type Journal Article
PMID (25658463)
Authors Richter M, Dayaram T, Gilmartin AG, Ganji G, Pemmasani SK, Van Der Key H, Shohet JM, Donehower LA, Kumar R
Title WIP1 phosphatase as a potential therapeutic target in neuroblastoma.
Journal PloS one
Vol 10
Issue 2
Date 2015
URL
Abstract Text The wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that negatively regulates multiple proteins involved in DNA damage response including p53, CHK2, Histone H2AX, and ATM, and it has been shown to be overexpressed or amplified in human cancers including breast and ovarian cancers. We examined WIP1 mRNA levels across multiple tumor types and found the highest levels in breast cancer, leukemia, medulloblastoma and neuroblastoma. Neuroblastoma is an exclusively TP53 wild type tumor at diagnosis and inhibition of p53 is required for tumorigenesis. Neuroblastomas in particular have previously been shown to have 17q amplification, harboring the WIP1 (PPM1D) gene and associated with poor clinical outcome. We therefore sought to determine whether inhibiting WIP1 with a selective antagonist, GSK2830371, can attenuate neuroblastoma cell growth through reactivation of p53 mediated tumor suppression. Neuroblastoma cell lines with wild-type TP53 alleles were highly sensitive to GSK2830371 treatment, while cell lines with mutant TP53 were resistant to GSK2830371. The majority of tested neuroblastoma cell lines with copy number gains of the PPM1D locus were also TP53 wild-type and sensitive to GSK2830371A; in contrast cell lines with no copy gain of PPM1D were mixed in their sensitivity to WIP1 inhibition, with the primary determinant being TP53 mutational status. Since WIP1 is involved in the cellular response to DNA damage and drugs used in neuroblastoma treatment induce apoptosis through DNA damage, we sought to determine whether GSK2830371 could act synergistically with standard of care chemotherapeutics. Treatment of wild-type TP53 neuroblastoma cell lines with both GSK2830371 and either doxorubicin or carboplatin resulted in enhanced cell death, mediated through caspase 3/7 induction, as compared to either agent alone. Our data suggests that WIP1 inhibition represents a novel therapeutic approach to neuroblastoma that could be integrated with current chemotherapeutic approaches.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 wild-type neuroblastoma predicted - sensitive Doxorubicin + GSK2830371 Preclinical Actionable In a preclinical study, GSK283071 and Adriamycin (doxorubicin) worked synergistically to inhibit proliferation of neuroblastoma cell lines carrying wild-type TP53 (PMID: 25658463). 25658463
TP53 wild-type neuroblastoma predicted - sensitive Carboplatin + GSK2830371 Preclinical Actionable In a preclinical study, GSK283071 and Paraplatin (carboplatin) worked synergistically to inhibit proliferation of neuroblastoma cell lines carrying wild-type TP53 (PMID: 25658463). 25658463
TP53 mutant neuroblastoma resistant GSK2830371 Preclinical Actionable In a preclinical study, neuroblastoma cell lines harboring TP53 mutations were resistant to GSK2830371 induced growth inhibition in culture (PMID: 25658463). 25658463
TP53 wild-type neuroblastoma predicted - sensitive GSK2830371 Preclinical Actionable In a preclinical study, GSK2830371 inhibited proliferation of neuroblastoma cell lines carrying wild-type TP53 in culture (PMID: 25658463). 25658463