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|Ref Type||Journal Article|
|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.|
|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.|
|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 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||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 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|