The putative oncogene CCNE1 (cyclin E1) is frequently amplified in human high-grade serous ovarian cancer. CCNE1 -amplified cancers tend to be wildtype for BRCA1 and BRCA2 and are associated with shorter survival and resistance to platinum-based chemotherapy. Cyclin E1 is an activating cofactor for cyclin-dependent kinases (CDK), which stimulate cell cycle progression through phosphorylation of the retinoblastoma (RB) protein and subsequent induction of E2F transcriptional activity (cyclin E1-RB-E2F signaling). Since BRCA1 and BRCA2 are known target genes of E2F transcription factors, we hypothesize that cyclin E1 signaling actively contributes to high DNA repair capacity and chemo-resistance in a BRCA1/2-dependent manner. We predict CCNE1 -amplified ovarian cancers to exhibit an “anti-BRCAness” phenotype. In two independent gene expression datasets, generated by TCGA and The Women9s Cancer Program at Cedars-Sinai, we found that CCNE1 -amplified ovarian cancers maintain higher levels of BRCA1 than CCNE1 -wildtype tumors. Moreover, we have employed genetic and pharmacological targeting approaches in order to assess if inhibition of cyclin E1-dependent signaling can induce BRCAness and restore chemo-sensitivity. Here, we show that pharmacological CDK inhibitors (CDKi) effectively shut down E2F-mediated transcription, resulting in downregulation of BRCA1 and BRCA2 in CDKi-treated cells. Long-term exposure of ovarian cancer cell lines to CDKi selected for cells with reduced dependency on cyclin E1, and genomic profiling revealed de novo DNA copy number changes which compensate for loss of cyclin E1 function. Importantly, CDKi-resistant subclones retained lower levels of BRCA1 and were significantly more sensitive to cisplatin than parental cell lines. Collectively, our results suggest that cyclin E1 signaling is required for BRCA1 expression and chemo-resistance. Currently available CDKi such as Dinaciclib, which is in a phase 3 clinical trial, may be useful to specifically sensitize CCNE1 -amplified ovarian cancers to cisplatin. Citation Format: Barbie Taylor-Harding, Hasmik Agadjanian, Paul Joseph Aspuria, Takako Mizuno, Dong-Joo Cheon, Sandra Orsulic, Beth Karlan, Christine Walsh, Wolf Ruprecht Wiedemeyer. Targeting chemo-resistance in CCNE1-amplified ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B48.