Oncotarget

Research Papers:

Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment

Laura R. H. Ip _, George Poulogiannis, Felipe Cia Viciano, Junko Sasaki, Satoshi Kofuji, Victoria J. Spanswick, Daniel Hochhauser, John A. Hartley, Takehiko Sasaki and Christina A. Gewinner

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Oncotarget. 2015; 6:10548-10562. https://doi.org/10.18632/oncotarget.3307

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Abstract

Laura R. H. Ip1, George Poulogiannis2, Felipe Cia Viciano1,3, Junko Sasaki4, Satoshi Kofuji4, Victoria J. Spanswick5, Daniel Hochhauser5, John A. Hartley5, Takehiko Sasaki4, Christina A. Gewinner1

1Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK

2The Institute of Cancer Research, Signalling and Cancer Metabolism, London, UK

3Faculty of Infectious and Tropical Diseases, Immunology and Infection Department, London School of Hygiene & Tropical Diseases, London, UK

4Department of Medical Biology, Akita University School of Medicine, Akita, Japan

5Cancer Research UK Drug-DNA Interaction Research Group, UCL Cancer Institute, University College London, London, UK

Correspondence to:

Christina Gewinner, e-mail: [email protected]

Keywords: inositol polyphosphate 4-phosphatase type II, INPP4B, DNA damage repair, PARP inhibition

Received: February 02, 2015     Accepted: February 08, 2015     Published: March 24, 2015

ABSTRACT

Treatment options for ovarian cancer patients remain limited and overall survival is less than 50% despite recent clinical advances. The lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) has been described as a tumor suppressor in the PI3K/Akt pathway with loss of expression found most pronounced in breast, ovarian cancer and melanoma. Using microarray technology we identified a DNA repair defect in INPP4B-deficient cells, which we further characterized by comet assays and quantification of γH2AX, RAD51 and 53BP1 foci formation. INPP4B loss resulted in significantly increased sensitivity towards PARP inhibition, comparable to loss of BRCA1 in two- and three-dimensional in vitro models, as well as in in vivo xenograft models. Mechanistically, we discovered that INPP4B forms a protein complex with the key players of DNA repair, ATR and BRCA1, in GST pulldown and 293T overexpression assays, and INPP4B loss affects BRCA1, ATM and ATR protein stability resulting in the observed DNA repair defect. Given that INPP4B loss has been found in 40% of ovarian cancer patients, this study provides the rationale for establishing INPP4B as a biomarker of PARP inhibitor response, and consequently offers novel therapeutic options for a significant subset of patients. Loss of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) results in a DNA repair defect due to concomitant loss of BRCA1, ATR and ATM and can be therapeutically targeted with PARP inhibitors.


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