Show simple item record

dc.contributor.authorChoi, Young Eunen_US
dc.contributor.authorBattelli, Chiaraen_US
dc.contributor.authorWatson, Jacquelineen_US
dc.contributor.authorLiu, Joyceen_US
dc.contributor.authorCurtis, Jenniferen_US
dc.contributor.authorMorse, Alexander N.en_US
dc.contributor.authorMatulonis, Ursula A.en_US
dc.contributor.authorChowdhury, Dipanjanen_US
dc.contributor.authorKonstantinopoulos, Panagiotis A.en_US
dc.date.accessioned2014-07-07T17:03:34Z
dc.date.issued2014en_US
dc.identifier.citationChoi, Young Eun, Chiara Battelli, Jacqueline Watson, Joyce Liu, Jennifer Curtis, Alexander N. Morse, Ursula A. Matulonis, Dipanjan Chowdhury, and Panagiotis A. Konstantinopoulos. 2014. “Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells.” Oncotarget 5 (9): 2678-2687.en
dc.identifier.issn1949-2553en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12406708
dc.description.abstractThe 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.en
dc.language.isoen_USen
dc.publisherImpact Journals LLCen
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058036/pdf/en
dash.licenseLAAen_US
dc.subjectEpithelial ovarian canceren
dc.subjectplatinumen
dc.subjectPARP inhibitorsen
dc.subjectHeat Shock Protein 90 inhibitorsen
dc.subjecthomologous recombinationen
dc.titleSublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cellsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalOncotargeten
dash.depositing.authorMatulonis, Ursula A.en_US
dc.date.available2014-07-07T17:03:34Z
dc.identifier.doi10.18632/oncotarget.1929
dash.contributor.affiliatedChowdhury, Dipanjan
dash.contributor.affiliatedKonstantinopoulos, Panagiotis
dash.contributor.affiliatedMatulonis, Ursula


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record