title: Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer.
abstract: Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.
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 College, Yantai 264000, China.
authors.forename: Dong
authors.initials: D
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: 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: 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: Xing
authors.initials: X
authors.lastname: Bian
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|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, Boston, MA 02115, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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.
authors.forename: Pixu
authors.initials: P
authors.lastname: Liu
authors.affiliation: Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
authors.forename: Hailing
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C531550:olaparib
keywords: BKM120; BRCA; Olaparib; combination therapy; ovarian cancer