title: Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non-triple-negative breast cancer cell lines.
abstract: PARP inhibitors, both as monotherapy and in combination with cytotoxic drugs, are currently undergoing clinical trials in several different cancer types. In this investigation, we compared the antiproliferative activity of two PARP/putative PARP inhibitors, i.e., olaparib and iniparib, in a panel of 14 breast cancer cell lines (seven tripe-negative and seven non-triple-negative). In almost all cell lines investigated, olaparib was a more potent inhibitor of cell growth than iniparib. Inhibition by both drugs was cell line-dependent and independent of the molecular subtype status of the cells, i.e., whether cells were triple-negative or non-triple negative. Although the primary target of PARP inhibitors is PARP1, no significant association was found between baseline levels of PARP1 activity and inhibition with either agent. Similarly, no significant correlation was evident between sensitivity and levels of CDK1, BRCA1 or miR-182. Combined addition of olaparib and either the CDK1 inhibitor, RO-3306 or a pan HER inhibitor (neratinib, afatinib) resulted in superior growth inhibition to that obtained with olaparib alone. We conclude that olaparib, in contrast to iniparib, is a strong inhibitor of breast cancer cell growth and may have efficacy in breast cancer irrespective of its molecular subtype, i.e., whether HER2-positive, estrogen receptor (ER)-positive or triple-negative. Olaparib, in combination with a selective CDK1 inhibitor or a pan HER inhibitor, is a potential new approach for treating breast cancer.
authors.affiliation: Education and Research Centre, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Aisling
authors.initials: A
authors.lastname: Pierce
authors.forename: Patricia M
authors.initials: PM
authors.lastname: McGowan
authors.forename: Maura
authors.initials: M
authors.lastname: Cotter
authors.forename: Maeve
authors.initials: M
authors.lastname: Mullooly
authors.forename: Norma
authors.initials: N
authors.lastname: O'Donovan
authors.forename: Sweta
authors.initials: S
authors.lastname: Rani
authors.forename: Lorraine
authors.initials: L
authors.lastname: O'Driscoll
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D035683:MicroRNAs / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D001549:Benzamides; D014408:Biomarkers, Tumor; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C090712:iniparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D016203:CDC2 Protein Kinase; C531550:olaparib
keywords: CDK1; PARP inhibitors; breast cancer; iniparib; olaparib; triple-negative