title: Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment.
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.
authors: Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK.
authors: Laura R H
authors: LR
authors: Ip
authors: The Institute of Cancer Research, Signalling and Cancer Metabolism, London, UK.
authors: George
authors: G
authors: Poulogiannis
authors: Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK.|Faculty of Infectious and Tropical Diseases, Immunology and Infection Department, London School of Hygiene & Tropical Diseases, London, UK.
authors: Felipe Cia
authors: FC
authors: Viciano
authors: Department of Medical Biology, Akita University School of Medicine, Akita, Japan.
authors: Junko
authors: J
authors: Sasaki
authors: Department of Medical Biology, Akita University School of Medicine, Akita, Japan.
authors: Satoshi
authors: S
authors: Kofuji
authors: Cancer Research UK Drug-DNA Interaction Research Group, UCL Cancer Institute, University College London, London, UK.
authors: Victoria J
authors: VJ
authors: Spanswick
authors: Cancer Research UK Drug-DNA Interaction Research Group, UCL Cancer Institute, University College London, London, UK.
authors: Daniel
authors: D
authors: Hochhauser
authors: Cancer Research UK Drug-DNA Interaction Research Group, UCL Cancer Institute, University College London, London, UK.
authors: John A
authors: JA
authors: Hartley
authors: Department of Medical Biology, Akita University School of Medicine, Akita, Japan.
authors: Takehiko
authors: T
authors: Sasaki
authors: Department of Cancer Biology, UCL Cancer Institute, University College London, London, UK.
authors: Christina A
authors: CA
authors: Gewinner
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair; D005260:Female; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D059467:Transcriptome; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase
keywords: DNA damage repair; INPP4B; PARP inhibition; inositol polyphosphate 4-phosphatase type II