Abstract B064: Therapeutic potential of CK1 delta inhibition in pancreatic and bladder cancer

Abstract

Abstract Gemcitabine has potent antitumor activity in several human cancers and represents the standard of care for advanced pancreatic ductal adenocarcinoma (PDAC). Nevertheless, despite aggressive treatment, long-term survival in PDAC is rare. Identification of specific drivers of PDAC is required to instruct the development of more targeted therapeutics. Casein kinase 1 delta (CK1δ) and epsilon (CK1ϵ) are serine/threonine kinases that regulate key effectors involved in tumor proliferation and differentiation such as Wnt-ß-catenin axis, PI3K/AKT signaling pathways, and p53 function. Aberrant regulation of the Wnt and p53 pathways occurs frequently in PDAC. Additionally, increased CK1δ expression has been found in bladder cancer, where gemcitabine is also a standard of care. This prompted us to test the antitumor effects of SR-3029, a potent, dual CK1δ/ϵ inhibitor developed in our laboratories in pancreatic and bladder cancer cells, and assess whether the combination of SR-3029 with gemcitabine would result in therapeutic synergy. Inhibition of cell proliferation (EC50) by SR-3029, both as a single agent and in combination with gemcitabine, was tested on a panel of several pancreatic and bladder cancer cells. Potent inhibition of proliferation was observed in a dose- and time-dependent fashion and SR-3029 acted in synergy with gemcitabine, as quantified by the Chou Talalay method. As described in our previous breast cancer studies, shRNAs targeting CK1δ and SR-3029 were sufficient to block colony formation of PDAC and bladder cancer cells. Gemcitabine acts a deoxycytidine analogue, converted into its active metabolite by deoxycytidine kinase (dCK) enzyme through a series of phosphorylation steps. The phosphorylated form of gemcitabine ultimately adds into the DNA strand terminating synthesis. dCK overexpression in pancreatic and bladder cancer tissues is associated with gemcitabine chemosensitivity. Searching for possible mechanisms explaining the synergy between SR-3029 and gemcitabine, we found that, upon treatment with SR-3029 and CK1δ knockdown, both dCK RNA and protein expression increased, possibly sensitizing to the antitumor effects of gemcitabine. We finally expanded our results in vivo and we evaluated the effect of SR-3029 alone and in combination with gemcitabine in an orthotopic mouse model of pancreatic cancer. Consistently, we observed a significant increase of tumor growth delay after gemcitabine plus SR-3029 treatment compared to gemcitabine alone. Importantly, this antitumor effect was accompanied by an increase of dCK expression in the xenografts. In summary, we believe that CK1δ may be a clinically relevant target in both pancreatic and bladder cancer, and in this setting SR-3029 holds promise as a future therapeutic option. Citation Format: Francesca Vena, Simon Bayle, Andrii Monastyrskyi, Derek Duckett, William Roush. Therapeutic potential of CK1 delta inhibition in pancreatic and bladder cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B064.