title: WIP1 phosphatase as a potential therapeutic target in neuroblastoma.
abstract: 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.
authors: Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania, United States of America.
authors: Mark
authors: M
authors: Richter
authors: Department of Molecular Virology and Microbiology and Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Tajhal
authors: T
authors: Dayaram
authors: Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania, United States of America.
authors: Aidan G
authors: AG
authors: Gilmartin
authors: Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania, United States of America.
authors: Gopinath
authors: G
authors: Ganji
authors: Ocimum Biosolutions Ltd., HUDA Techno Enclave, Hyderabad, AP, India.
authors: Sandhya Kiran
authors: SK
authors: Pemmasani
authors: Platform Technology & Science, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania, United States of America.
authors: Harjeet
authors: H
authors: Van Der Key
authors: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Jason M
authors: JM
authors: Shohet
authors: Department of Molecular Virology and Microbiology and Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Lawrence A
authors: LA
authors: Donehower
authors: Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania, United States of America.
authors: Rakesh
authors: R
authors: Kumar
mesh_terms: D000483:Alleles; D000631:Aminopyridines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D004151:Dipeptides; C587624:GSK2830371; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C