title: MK-2206 sensitizes BRCA-deficient epithelial ovarian adenocarcinoma to cisplatin and olaparib.
abstract: Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation of the AKT pathway promotes platinum resistance while inhibition of AKT sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus a defect in the homologous recombination (HR) repair pathway, demonstrate greater clinical response to platinum and olaparib therapy than patients with BRCA wild-type EOC. MK-2206, an allosteric inhibitor of AKT phosphorylation, sensitizes a variety of cell types to various anticancer agents and is currently undergoing phase II trials as monotherapy for platinum-resistant ovarian, fallopian tube, and peritoneal cancer. This study examines the differential effects of AKT inhibition with cisplatin and olaparib therapy in BRCA1/2-deficient versus wild-type EOC.
  
  
  
  PEO1, a chemosensitive BRCA2-mutant serous ovarian adenocarcinoma, and PEO4, a reverted BRCA2-proficient line from the same patient after the development of chemotherapeutic resistance, were primarily used for the study. In PEO1, MK-2206 demonstrated moderate to strong synergism with cisplatin and olaparib at all doses, while demonstrating antagonism at all doses in PEO4.
  
  
  
  Baseline phospho-AKT activity in untreated cells was upregulated in both BRCA1- and 2-deficient cell lines. MK-2206 prevented cisplatin- and olaparib-induced AKT activation in the BRCA2-deficient PEO1 cells. We propose that BRCA-deficient EOC cells upregulate baseline AKT activity to enhance survival in the absence of HR. Higher AKT activity is also required to withstand cytotoxic agent-induced DNA damage, leading to strong synergism between MK-2206 and cisplatin or olaparib therapy in BRCA-deficient cells.
  
  
  
  MK-2206 shows promise as a chemosensitization agent in BRCA-deficient EOC and merits clinical investigation in this patient population.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA. margaret.whicker@yale.edu.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Whicker
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA.
authors.forename: Z Ping
authors.initials: ZP
authors.lastname: Lin
authors.affiliation: Section of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Hanna
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
authors.affiliation: Section of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Ratner
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D010793:Phthalazines; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin; C531550:olaparib
keywords: AKT inhibitors; BRCA; Epithelial ovarian cancer; MK-2206; PARP inhibitors