5500 Background: The aim of our study was to develop and validate a gene expression signature predictive for chemoresponse in advanced stage serous papillary ovarian cancer. Methods: Gene expression profiling was performed on 52 chemonaive, microdissected advanced stage, high-grade papillary serous ovarian cancers using Affymetrix whole-genome microarrays. Patient samples were grouped based on chemoresponse. 19 nonresponders were refractory to chemotherapy, 14 responders relapsing 6 months were considered chemosensitive. Each group was divided into training/validation sets. To generate a predictive gene signature, class prediction algorithms were applied to genes differentially expressed between chemosensitive/resistant or chemosensitive/refractory tumors (p<0.001) using leave-one-out cross-validation. Array validation was performed by qRT-PCR. Select genes underwent biological validation in a series of ovarian cancer cell lines. Results: 31 genes predictive for resistance and 105 genes predictive for refractory to chemotherapy were identified. Percentages of arrays accurately predicted in independent validation sets were 90% (9/10) for resistant and 92% (12/13) for refractory gene signatures. Correlations between microarray/qRT-PCR data were robust for both resistant (17/23 genes) and refractory gene signatures (25/34 genes). Data mining of the predictive signatures using PathwayStudio software identified several biological processes (collagen regulation, apoptosis, cell survival, and DNA repair) implicated in conferring resistance to chemotherapy. We transiently transfected RNAi molecules to silence several signature genes and determine their contribution to taxol/cisplatin sensitivity in a series ofl ovarian cancer cell lines. Preliminary data showed DUSP1 gene expression knockdown potentiated cisplatin sensitivity in SKOV3/OVCA429 cell lines, while POLH knockdown potentiated cisplatin sensitivity in OVCA429/OVCA420 cell lines. Conclusions: A gene expression signature predicts for chemoresponse in ovarian cancers, and has identified novel targets of biological/therapeutic interest. No significant financial relationships to disclose.