Pilot: Inhibiting CK1a increases the Efficacy of Enzalutamide in Castration-resistant

Principal Investigator: Liu, Jinghui 18.2 2. PROJECT TITLE: Inhibiting CK1a increases the efficacy of Enzalutamide in castration-resistant prostate cancer ABSTRACT: Background: Androgen deprivation therapy is the first line of therapy for localized prostate cancer (PCa), but most patients will eventually develop castration-resistant PCa (CRPC). Enzalutamide (ENZ), a second- generation androgen receptor (AR) antagonist, has significantly increased CRPC patient survival. However, resistance remains a prominent obstacle in treatment, illustrating the urgent need to develop new approaches to increase ENZ efficacy. CK1α participates in extensive regulatory roles in numerous cellular processes including DNA-processing and repair, autophagy, cell cycle and apoptosis. Mutations and alterations of CK1α are detected in various tumor entities including kidney, breast, pancreas, and ovarian cancers. Moreover, CK1α expression is associated with poorer overall survival in cancer patients. Yet, whether and how CK1α is involved in PCa development and ENZ treatment response is unknown. The objective of this study is to evaluate CK1α as a novel therapeutic target to increase the efficacy of ENZ treatment in CRPC. Our central hypothesis is that inhibition of CK1α will result in DNA damage response (DDR) signaling restoration while simultaneously decreasing AR signaling, thus increasing ENZ- induced cell death and growth arrest. Mechanistically, CK1α is a direct negative regulator of ataxia- telangiectasia mutated (ATM), a primary initiator of DDR, which is obstructed in ENZ resistant cells. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DDR checkpoint signaling, and thus increasing ENZ-induced DNA damage related cell death. Additionally, CK1α contributes to AR and AR variants (AR-v) transcriptional activity, by phosphorylating histone deacetylase 3 (HDAC3) and inactivating NCoR-HDAC3 complex. Inhibiting CK1α hinders AR signaling and further enhances DDR checkpoint activity, thus increasing ENZ-induced cell death and cell growth arrest. Our hypothesis will be tested by pursuing two Specific Aims (1) Determine functional significance of CK1α-associated ATM phosphorylation and ENZ treatment response. (2) Dissect how CK1α phosphorylation of HDAC3 regulates AR signaling and ENZ treatment response. Study Design: These complementary aims will be accomplished by using multiple PCa cell lines to ensure that our findings are not cell line specific and will validate key findings in clinically relevant tissues. The proposed research is highly impactful with strong translational potentials in prostate cancer research. If we validate our hypothesis, the expected results will support the opening of an immediate clinical trial using the combination of CK1α inhibitor A51 with ENZ for treatment of CRPC. Institutional Research Grant American Cancer Society – January 2019