Addiction to protein kinase Cɩdue to PRKCI gene amplification can be exploited for an aptamer-based targeted therapy in ovarian cancer

PRKCI,the gene for protein kinase Cι(PKCι),is frequently amplified in ovarian cancer and recent studies have shown that PKCιparticipates in ovary tumorigenesis.However,it is unknown whether PKCιis differentially involved in the growth/survival between PRKCI-amplified and non-amplified ovarian cancer cells.In this study,we analyzed ovarian cancer patient dataset and revealed that PRKCI is the only PKC family member significantly amplified in ovarian cancer and PRKCI amplification is associated with higher PKCιexpression.Using a panel of ovarian cancer cell lines,we found that abundance of PKCιis generally associated with PRKCI amplification.Interestingly,silencing PKCιled to apoptosis in PRKCI-amplified ovarian cancer cells but not in those without PRKCI amplification,thus indicating an oncogenic addiction to PKCɩin PRKCI-amplified cells.Since small-molecule inhibitors characterized to selectively block atypical PKCs did not offer selectivity nor sensitivity in PRKCI-amplified ovarian cancer cells and were even cytotoxic to non-cancerous ovary surface or fallopian tube epithelial cells,we designed an EpCAM aptamer-PKCιsiRNA chimera(EpCAM-siPKCιaptamer).EpCAM-siPKCιaptamer not only effectively induced apoptosis of PRKCI-amplified ovarian cancer cells but also greatly deterred intraperitoneal tumor development in xenograft mouse model.This study has demonstrated a precision medicine-based strategy to target a subset of ovarian cancer that contains PRKCI amplification and shown that the EpCAM aptamerdelivered PKCιsiRNA may be used to suppress such tumors.