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Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib.

Wilson AJ, Sarfo-Kantanka K, Barrack T, Steck A, Saskowski J, Crispens MA, Khabele D
Gynecol Oncol. 2016 143 (1): 143-151

PMID: 27444036 · PMCID: PMC5031537 · DOI:10.1016/j.ygyno.2016.07.088

OBJECTIVE - Homologous recombination (HR) proficient ovarian cancers, including CCNE1 (cyclin E)-amplified tumors, are resistant to poly (ADP-ribose) polymerase inhibitors (PARPi). Histone deacetylase inhibitors (HDACi) are effective in overcoming tumor resistance to DNA damaging drugs. Our goal was to determine whether panobinostat, a newly FDA-approved HDACi, can sensitize cyclin E, HR-proficient ovarian cancer cells to the PARPi olaparib.

METHODS - Expression levels of CCNE1 (cyclin E), BRCA1, RAD51 and E2F1 in ovarian tumors and cell lines were extracted from The Cancer Genome Atlas (TCGA) and Broad-Novartis Cancer Cell Line Encyclopedia (CCLE). In HR-proficient ovarian cancer cell line models (OVCAR-3, OVCAR-4, SKOV-3, and UWB1.289+BRCA1 wild-type), cell growth and viability were assessed by sulforhodamine B and xenograft assays. DNA damage and repair (pH2AX and RAD51 co-localization and DRGFP reporter activity) and apoptosis (cleaved PARP and cleaved caspase-3) were assessed by immunofluorescence and Western blot assays.

RESULTS - TCGA and CCLE data revealed positive correlations (Spearman) between cyclin E E2F1, and E2F1 gene targets related to DNA repair (BRCA1 and RAD51). Panobinostat downregulated cyclin E and HR repair pathway genes, and reduced HR efficiency in cyclin E-amplified OVCAR-3 cells. Further, panobinostat synergized with olaparib in reducing cell growth and viability in HR-proficient cells. Similar co-operative effects were observed in xenografts, and on pharmacodynamic markers of HR repair, DNA damage and apoptosis.

CONCLUSIONS - These results provide preclinical rationale for using HDACi to reduce HR in cyclin E-overexpressing and other types of HR-proficient ovarian cancer as a means of enhancing PARPi activity.

Copyright © 2016 Elsevier Inc. All rights reserved.

MeSH Terms (14)

Antineoplastic Agents Cyclin E DNA Repair Drug Synergism Female Homologous Recombination Humans Hydroxamic Acids Indoles Oncogene Proteins Ovarian Neoplasms Panobinostat Phthalazines Piperazines

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