title: Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes.
abstract: Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes.
  
  
  
  We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib. The effect of BKM120 as a single-agent or in combination with Olaparib was evaluated by Cell Count Kit (CCK8) assay, immunoblotting, comet assay, flow cytometry and immunofluorescence staining assay. The combination indexes for synergistic effect on cell viability were calculated with the Chou-Talalay method. Ex vivo cultured ovarian cancer tissues from patients were analyzed by histological and immunohistochemical analyses.
  
  
  
  Combined inhibition of PI3K and PARP effectively synergized to block the growth of three wild-type PIK3CA ovarian cancer cell lines and explants of a primary ovarian tumor specimen. Mechanistically, dual blockade of PI3K and PARP in these ovarian cancer cell lines resulted in substantially attenuated PI3K/AKT/mTOR signaling, impaired DNA damage response and deficient homologous recombination repair, with remarkable BRCA downregulation.
  
  
  
  The combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib may be effective in ovarian cancers with a broader spectrum of cancer-associated genetic alterations but not limited to those with mutant PIK3CA or BRCA genes. BRCA downregulation may be a potential biomarker for the effective response to the proposed combination treatment.
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China; Department of Histology and Embryology, Binzhou Medical University, Yantai 264000, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Obstetrics & Gynecology, The Second Hospital of Dalian Medical University, Dalian 116044, China.
authors.forename: Chengbo
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Roberts
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jean_zhao@dfci.harvard.edu.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China. Electronic address: hailingcheng_dmu@163.com.
authors.forename: Hailing
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China. Electronic address: pixu_liu@dmu.edu.cn.
authors.forename: Pixu
authors.initials: P
authors.lastname: Liu
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004357:Drug Synergism; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D058534:Class I Phosphatidylinositol 3-Kinases; D009025:Morpholines; D058539:Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; C571178:NVP-BKM120; C484760:PIK3CA protein, human; C531550:olaparib
keywords: BKM120; BRCA; Combination therapy; Olaparib; Ovarian cancer