title: Doubling down on the PI3K-AKT-mTOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness.
abstract: Phosphoinositide 3-kinase (PI3K) pathway, in addition to its pro-proliferative and antiapoptotic effects on tumor cells, contributes to DNA damage repair (DDR). We hypothesized that GDC-0980, a dual PI3K-mammalian target of rapamycin (mTOR) inhibitor, would induce an efficient antitumor effect in BRCA-competent triple negative breast cancer (TNBC) model when combined with ABT888 and carboplatin. Mechanism-based in vitro studies demonstrated that GDC-0980 treatment alone or in combination led to DNA damage (increased pγH2AX(S139); Western blot, immunofluorescence), gain in poly ADP-ribose (PAR), and a subsequent sensitization of BRCA-competent TNBC cells to ABT888 plus carboplatin with a time-dependent 1) decrease in proliferation signals (pAKTT308/S473, pP70S6KT421/S424, pS6RPS235/236), PAR/poly(ADP-ribose) polymerase (PARP) ratios, PAR/pγH2AX ratios, live/dead cell ratios, cell cycle progression, and three-dimensional clonogenic growths and 2) increase in apoptosis markers (cleaved caspases 3 and 9, a pro-apoptotic BH3-only of Bcl-2 family (BIM), cleaved PARP, annexin V). The combination was effective in vitro in BRCA-wild-type PIK3CA-H1047R-mutated BT20 and PTEN-null HCC70 cells. The combination blocked the growth of established xenograft tumors by 80% to 90% with a concomitant decrease in tumor Ki67, CD31, phosphorylated vascular endothelial growth factor receptor, pS6RPS235/236, and p4EBP1T37/46 as well as an increase in cleaved caspase 3 immunohistochemistry (IHC) levels. Interestingly, a combination with GDC-0941, a pan-PI3K inhibitor, failed to block the tumor growth in MDA-MB231. Results demonstrate that the dual inhibition of PI3K and mTOR regulates DDR. In a BRCA-competent model, GDC-0980 enhanced the antitumor activity of ABT888 plus carboplatin by inhibiting both tumor cell proliferation and tumor-induced angiogenesis along with an increase in the tumor cell apoptosis. This is the first mechanism-based study to demonstrate the integral role of the PI3K-AKT-mTOR pathway in DDR-mediated antitumor action of PARP inhibitor in TNBC.
authors.affiliation: Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD ; Department of Internal Medicine, University of South Dakota, Vermillion, SD.
authors.forename: Pradip
authors.initials: P
authors.lastname: De
authors.affiliation: Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Carlson
authors.affiliation: Genentech, South San Francisco, CA.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.affiliation: Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD ; Department of Internal Medicine, University of South Dakota, Vermillion, SD.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Leyland-Jones
authors.affiliation: Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, SD ; Department of Internal Medicine, University of South Dakota, Vermillion, SD.
authors.forename: Nandini
authors.initials: N
authors.lastname: Dey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D016190:Carboplatin; D053148:Caspase 3; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C087000:EIF4EBP1 protein, human; C521013:veliparib; C546842:MTOR protein, human; C494918:AKT1 protein, human