title: Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells.
abstract: The promise of PARP-inhibitors(PARPis) in the management of epithelial ovarian cancer(EOC) is tempered by the fact that approximately 50% of patients with homologous recombination (HR)-proficient tumors do not respond well to these agents. Combination of PARPis with agents that inhibit HR may represent an effective strategy to enhance their activity in HR-proficient tumors. Using a bioinformatics approach, we identified that heat shock protein 90 inhibitors(HSP90i) may suppress HR and thus revert HR-proficient to HR-deficient tumors. Analysis of publicly available gene expression data showed that exposure of HR-proficient breast cancer cell lines to HSP90i 17-AAG(17-allylamino-17-demethoxygeldanamycin) downregulated HR, ATM and Fanconi Anemia pathways. In HR-proficient EOC cells, 17-AAG suppressed HR as assessed using the RAD51 foci formation assay and this was further confirmed using the Direct Repeat-GFP reporter assay. Furthermore, 17-AAG downregulated BRCA1 and/or RAD51 protein levels, and induced significantly more γH2AX activation in combination with olaparib compared to olaparib alone. Finally, sublethal concentrations of 17-AAG sensitized HR-proficient EOC lines to olaparib and carboplatin but did not affect sensitivity of the HR-deficient OVCAR8 line arguing that the 17-AAG mediated sensitization is dependent on suppression of HR. These results provide a preclinical rationale for using a combination of olaparib/17-AAG in HR-proficient EOC.
authors.affiliation: Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Choi
authors.forename: Chiara
authors.initials: C
authors.lastname: Battelli
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Watson
authors.forename: Joyce
authors.initials: J
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Curtis
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Morse
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059767:Recombinational DNA Repair / Q000187:drug effects* / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C112765:tanespimycin; D016190:Carboplatin; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib