Oncotarget

Research Papers:

Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells

Young Eun Choi, Chiara Battelli, Jacqueline Watson, Joyce Liu, Jennifer Curtis, Alexander N. Morse, Ursula A. Matulonis, Dipanjan Chowdhury and Panagiotis A. Konstantinopoulos _

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Oncotarget. 2014; 5:2678-2687. https://doi.org/10.18632/oncotarget.1929

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Abstract

Young Eun Choi1, Chiara Battelli2, Jacqueline Watson1, Joyce Liu3, Jennifer Curtis3, Alexander N. Morse4, Ursula A. Matulonis3, Dipanjan Chowdhury1, Panagiotis A. Konstantinopoulos1,3

1 Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School

2 Maine Center for Cancer Medicine, Scarborough, Maine

3 Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana Farber Cancer Institute, Harvard Medical School

4 New York University Global Institute of Public Health

Correspondence:

Panagiotis Konstantinopoulos, email:

Keywords: Epithelial ovarian cancer, platinum, PARP inhibitors, Heat Shock Protein 90 inhibitors, homologous recombination

Received: February 23, 2014 Accepted: April 30, 2014 Published: April 30, 2014

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.


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