Advertisement

Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes

  • Author Footnotes
    1 The first two authors contributed equally to the work.
    Dong Wang
    Footnotes
    1 The first two authors contributed equally to the work.
    Affiliations
    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
    Search for articles by this author
  • Author Footnotes
    1 The first two authors contributed equally to the work.
    Chengbo Li
    Footnotes
    1 The first two authors contributed equally to the work.
    Affiliations
    Department of Obstetrics & Gynecology, The Second Hospital of Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Yuan Zhang
    Affiliations
    Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Min Wang
    Affiliations
    Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Nan Jiang
    Affiliations
    Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Lin Xiang
    Affiliations
    Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Ting Li
    Affiliations
    Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Thomas M. Roberts
    Affiliations
    Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
    Search for articles by this author
  • Jean J. Zhao
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
    Search for articles by this author
  • Hailing Cheng
    Correspondence
    Corresponding authors.
    Affiliations
    Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Pixu Liu
    Correspondence
    Corresponding authors.
    Affiliations
    Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
    Search for articles by this author
  • Author Footnotes
    1 The first two authors contributed equally to the work.

      Highlights

      • PI3K inhibition induces BRCA downregulation in wild-type PIK3CA ovarian cancer.
      • PI3K and PARP inhibitors synergistically suppress ovarian cancer cell growth.
      • BRCA downregulation following PI3K inhibition may predict PARP inhibitor response.

      Abstract

      Objective

      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.

      Methods

      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.

      Results

      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.

      Conclusions

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Liu P.
        • Cheng H.
        • Roberts T.M.
        • Zhao J.J.
        Targeting the phosphoinositide 3-kinase pathway in cancer.
        Nat. Rev. Drug Discov. 2009; 8: 627-644
        • Fruman D.A.
        • Rommel C.
        PI3K and cancer: lessons, challenges and opportunities.
        Nat. Rev. Drug Discov. 2014; 13: 140-156
        • The Cancer Genome Atlas Network
        Integrated genomic analyses of ovarian carcinoma.
        Nature. 2011; 474: 609-615
        • Levine D.A.
        • Bogomolniy F.
        • Yee C.J.
        • Lash A.
        • Barakat R.R.
        • Borgen P.I.
        • et al.
        Frequent mutation of the PIK3CA gene in ovarian and breast cancers.
        Clin. Cancer Res. 2005; 11: 2875-2878
        • Banerjee S.
        • Kaye S.B.
        New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential.
        Clin. Cancer Res. 2013; 19: 961-968
        • Carden C.P.
        • Stewart A.
        • Thavasu P.
        • Kipps E.
        • Pope L.
        • Crespo M.
        • et al.
        The association of pi3 kinase signaling and chemoresistance in advanced ovarian cancer.
        Mol. Cancer Ther. 2012; 11: 1609-1617
        • Rexer B.N.
        • Chanthaphaychith S.
        • Dahlman K.
        • Arteaga C.L.
        Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells.
        Breast Cancer Res. 2014; 16: R9
        • Roper J.
        • Sinnamon M.J.
        • Coffee E.M.
        • Belmont P.
        • Keung L.
        • Georgeon-Richard L.
        • et al.
        Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer.
        Cancer Lett. 2014; 347: 204-211
        • Rodon J.
        • Brana I.
        • Siu L.L.
        • De Jonge M.J.
        • Homji N.
        • Mills D.
        • et al.
        Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors.
        Investig. New Drugs. 2014; 32: 670-681
        • Bedard P.L.
        • Tabernero J.
        • Janku F.
        • Wainberg Z.A.
        • Paz-Ares L.
        • Vansteenkiste J.
        • et al.
        A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.
        Clin. Cancer Res. 2014; 730-738
        • Burger M.T.
        • Pecchi S.
        • Wagman A.
        • Ni Z.
        • Knapp M.
        • Hendrickson T.
        • et al.
        Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer.
        ACS Med. Chem. Lett. 2011; 2: 774-779
        • Brachmann S.M.
        • Kleylein-Sohn J.
        • Gaulis S.
        • Kauffmann A.
        • Blommers M.J.J.
        • Kazic-Legueux M.
        • et al.
        Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations.
        Mol. Cancer Ther. 2012; 11: 1747-1757
        • Ibrahim Y.H.
        • Garcia-Garcia C.
        • Serra V.
        • He L.
        • Torres-Lockhart K.
        • Prat A.
        • et al.
        PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition.
        Cancer Discov. 2012; 2: 1036-1047
        • Juvekar A.
        • Burga L.N.
        • Hu H.
        • Lunsford E.P.
        • Ibrahim Y.H.
        • Balmana J.
        • et al.
        Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.
        Cancer Discov. 2012; 2: 1048-1063
        • Bolton K.L.
        • Chenevix-Trench G.
        • Goh C.
        • Sadetzki S.
        • Ramus S.J.
        • Karlan B.Y.
        • Lambrechts D.
        • et al.
        Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.
        JAMA. 2012; 307: 382-390
        • Audeh M.W.
        • Carmichael J.
        • Penson R.T.
        • Friedlander M.
        • Powell B.
        • Bell-McGuinn K.M.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 245-251
        • Kim G.
        • Ison G.
        • McKee A.E.
        • Zhang H.
        • Tang S.
        • Gwise T.
        • et al.
        FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy.
        Clin. Cancer Res. 2015; 21: 4257-4261
        • Tutt A.
        • Robson M.
        • Garber J.E.
        • Domchek S.M.
        • Audeh M.W.
        • Weitzel J.N.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 235-244
        • Gelmon K.A.
        • Tischkowitz M.
        • Mackay H.
        • Swenerton K.
        • Robidoux A.
        • Tonkin K.
        • et al.
        Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
        Lancet Oncol. 2011; 12: 852-861
        • Wang D.
        • Wang M.
        • Jiang N.
        • Zhang Y.
        • Bian X.
        • Wang X.
        • et al.
        Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer.
        Oncotarget. 2016; 7: 13153-13166
        • Stordal B.
        • Timms K.
        • Farrelly A.
        • Gallagher D.
        • Busschots S.
        • Renaud M.
        • et al.
        BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.
        Mol. Oncol. 2013; 7: 567-579
        • Li L.
        • Chang W.
        • Yang G.
        • Ren C.
        • Park S.
        • Karantanos T.
        • et al.
        Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer.
        Sci. Signal. 2014; 7 (ra47-ra47)
        • Junttila T.T.
        • Akita R.W.
        • Parsons K.
        • Fields C.
        • Lewis P.G.
        • Friedman L.S.
        • et al.
        Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.
        Cancer Cell. 2009; 15: 429-440
        • Chou T.C.
        Drug combination studies and their synergy quantification using the Chou-Talalay method.
        Cancer Res. 2010; 70: 440-446
        • Du Y.
        • Yamaguchi H.
        • Wei Y.
        • Hsu J.L.
        • Wang H.L.
        • Hsu Y.H.
        • et al.
        Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.
        Nat. Med. 2016; 22: 194-201
        • Dean J.L.
        • McClendon A.K.
        • Hickey T.E.
        • Butler L.M.
        • Tilley W.D.
        • Witkiewicz A.K.
        • et al.
        Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors.
        Cell Cycle. 2012; 11: 2756-2761
        • Sun C.K.
        • Zhang F.
        • Xiang T.
        • Chen Q.
        • Pandita T.K.
        • Huang Y.
        • et al.
        Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers.
        Oncotarget. 2014; 5: 3375-3385
        • Mukhopadhyay A.
        • Elattar A.
        • Cerbinskaite A.
        • Wilkinson S.J.
        • Drew Y.
        • Kyle S.
        • et al.
        Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors.
        Clin. Cancer Res. 2010; 16: 2344-2351
        • Gonzalez-Billalabeitia E.
        • Seitzer N.
        • Song S.J.
        • Song M.S.
        • Patnaik A.
        • Liu X.S.
        • et al.
        Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.
        Cancer Discov. 2014; 4: 896-904
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • Tutt A.N.
        • Johnson D.A.
        • Richardson T.B.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Bryant H.E.
        • Schultz N.
        • Thomas H.D.
        • Parker K.M.
        • Flower D.
        • Lopez E.
        • Helleday T.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
        Nature. 2005; 434: 913-917
        • Edwards S.L.
        • Brough R.
        • Lord C.J.
        • Natrajan R.
        • Vatcheva R.
        • Levine D.A.
        • et al.
        Resistance to therapy caused by intragenic deletion in BRCA2.
        Nature. 2008; 451: 1111-1115