title: Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.
abstract: Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi), become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi)). Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG)-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF) 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.
authors.affiliation: Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Ramat Gan 52621, Israel.|Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Yalon
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Liron
authors.initials: L
authors.lastname: Tuval-Kochen
authors.affiliation: Neufeld Cardiac Research Institute, Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Castel
authors.affiliation: Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: Itai
authors.initials: I
authors.lastname: Moshe
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Mazal
authors.affiliation: Department of Surgery, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Osher
authors.initials: O
authors.lastname: Cohen
authors.affiliation: Department of Pathology, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.affiliation: Department of Pathology, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Kineret
authors.initials: K
authors.lastname: Rosenblatt
authors.affiliation: Department of Pathology, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Aviel-Ronen
authors.affiliation: Department of Pathology, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Ginette
authors.initials: G
authors.lastname: Schiby
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering, New York 10021, United States of America.
authors.forename: Joachim
authors.initials: J
authors.lastname: Yahalom
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Pfeffer
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Lawrence
authors.affiliation: Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Ramat Gan 52621, Israel.|Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Toren
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Paglin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D019008:Drug Resistance, Neoplasm; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D013866:Thioguanine / Q000008:administration & dosage; D000077337:Vorinostat; D015431:Weight Loss
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D001562:Benzimidazoles; D002352:Carrier Proteins; D015852:Eukaryotic Initiation Factor-2; D006877:Hydroxamic Acids; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C486715:TXNIP protein, human; C521013:veliparib; D000077337:Vorinostat; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D013866:Thioguanine