Abstract A28: Casein kinase 1{epsilon} (CSNK1{epsilon}) is a synthetic lethal target in MYC-driven ovarian cancer

In this study, 45 genes were selected for further study based on druggability, involvement in cancer pathways, and differential toxicity. We focused on 23 genes based on their expression pattern in ovarian cancers, of which 9 genes were identified to exhibit strong synthetic lethality in ovarian cancer cells with cMYC overexpression. Casein kinase 1 (CSNK1) was one of the top candidates and was therefore selected for subsequent validation and further analysis. Knock-down of CSNK1 had minimal toxicity in human fibroblasts, suggesting the possibility of a good therapeutic window.Using qPCR and immunohistochemistry analysis of 55 frozen samples from ovarian cancer patients, we showed significant correlation of MYC and CSNK1 expression. Moreover, analysis of publically available microarray data showed that patients with high CSNK1 expression are associated with poorer survival. Next, we performed functional validation in two sets of ovarian cancer cell lines with either high-MYC expression (IGROV-1 and TOV112D) or low-MYC expression (CaOV3 and DOV13). Using RNAi and small molecule inhibitors (IC261, PF-670462, PF-4800567), we demonstrated that CSNK1 inhibition reduced cell viability and attenuated the WNT and SHH target pathways specifically in cells with high-MYC expression. Treatment with the CSNK1 specific inhibitor, PF-4800567, further revealed that upregulation of CSNK1 could be a potential mechanism of resistance. Finally, the growth of TOV112D cells (high MYC) in a tumor x...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research