Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
PloS one	10	2	2015	e0115635	PLoS One

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	Carboplatin + GSK2830371	Preclinical	Actionable	In a preclinical study, GSK2830371 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
TP53 wild-type	neuroblastoma	predicted - sensitive	Doxorubicin + GSK2830371	Preclinical	Actionable	In a preclinical study, GSK2830371 and Adriamycin (doxorubicin) worked synergistically to inhibit proliferation of neuroblastoma cell lines carrying wild-type TP53 (PMID: 25658463).	25658463