Abstract A28: Casein kinase 1ε (CSNK1ε) is a synthetic lethal target in MYC-driven ovarian cancer
Authors: Lui Goldie Y. L. , Schaub Franz , Agrawal Shaifali , Kitatani Kazuyuki , Kemp Christopher J. , Toyoshima Masafumi , Grandori Carla 
Published: December 2017

Abstract
The MYC family of oncogenes encodes transcription factors that are master regulators of cell proliferation and is a central driver in many human cancers. Without obvious druggable domains, direct inhibition of MYC by small molecules has remained a challenge. An alternative strategy is to exploit the concept of synthetic lethality, where specific combinations of mutations lead to cell death, while each mutation alone is not essential for survival. Targeting these synthetic lethal interactions provides an opportunity to minimize toxicity by sparing normal cells without mutations. Given that MYC amplification is reported in approximately 40% of ovarian cancers and is a leading cause of gynecologic cancer-related deaths, identifying novel therapeutic targets for this disease is of urgent clinical importance.
We previously utilized a high-throughput functional genomics approach to identify 149 synthetic lethal candidates with cMYC overexpression using isogenic human foreskin fibroblast cells. 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 1ε (CSNK1ε) was one of the top candidates and was therefore selected for subsequent validation and further analysis. Knock-down of CSNK1ε 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 CSNK1ε expression. Moreover, analysis of publically available microarray data showed that patients with high CSNK1ε 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 CSNK1ε inhibition reduced cell viability and attenuated the WNT and SHH target pathways specifically in cells with high-MYC expression. Treatment with the CSNK1ε specific inhibitor, PF-4800567, further revealed that upregulation of CSNK1δ could be a potential mechanism of resistance. Finally, the growth of TOV112D cells (high MYC) in a tumor xenograft model was significantly inhibited by daily treatment with IC61.
These findings reveal a new strategy to target the undruggable MYC oncogene through synthetic lethal interactions in MYC-driven ovarian cancer. Targeting CSNK1ε offers a novel therapeutic approach to complement traditional chemotherapies currently used to treat this disease in the clinic.
Citation Format: Goldie Y. L. Lui, Franz Schaub, Shaifali Agrawal, Kazuyuki Kitatani, Christopher J. Kemp, Masafumi Toyoshima, Carla Grandori. Casein kinase 1ε (CSNK1ε) is a synthetic lethal target in MYC-driven ovarian cancer [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A28.