Abstract 950: New strategy to sensitize pancreatic and bladder cancer to gemcitabine

Abstract

Abstract Pancreatic Ductal Adenocarcinoma (PDAC), the major histological subtype of pancreatic cancer displays few symptoms for early detection and the majority of PDAC patients are diagnosed with advanced or metastatic disease. PDAC patients with advanced disease lack durable responses to chemotherapy and have a dismal prognosis. Gemcitabine is the cornerstone of care for advanced and metastatic PDAC. While the underlying mechanisms leading to gemcitabine resistance are likely to be multifactorial, there is a strong association between activating gemcitabine metabolism pathways and clinical outcome. Accordingly, strategies that lead to upregulation of signaling pathways and enzymes involved in generating the active metabolite may lead to improved outcome in PDAC. We have developed a potent, selective, small molecule inhibitor of casein kinase-1 delta (CK1δ) and demonstrated that inhibition of CK1δ activity specifically compromises the growth, survival and invasion of breast cancer cells that overexpress CK1δ. Notably, our lead compound, SR-3029 provokes pre-clinical tumor regression of triple negative breast cancer (TNBC), including lung metastatic TNBC and basal-like PDX breast cancer models. We observed that CK1δ is upregulated in other cancers including bladder cancer and demonstrated that SR-3029 acts in synergy with DNA damaging cytotoxic agents. Notably, the combination of gemcitabine with SR-3029 resulted in synergistic antiproliferative activity and impaired colony formation in both pancreatic and bladder cancer cells. Mechanistic studies demonstrate that silencing CK1δ or inhibition of CK1δ activity by SR-3029 induces a significant upregulation of deoxycytidine kinase (DCK; rate limiting enzyme for gemcitabine activation) both at the RNA and protein levels, which results in increased cellular DCK and its active gemcitabine metabolite. We evaluated the effect of SR-3029 alone and in combination with gemcitabine in an orthotopic pancreatic tumor mouse model and observed much improved tumor growth inhibition with combination treatment, concomitant with increased expression of DCK. In conclusion, our study suggests that CK1δ plays signaling roles in DNA metabolism and the combination of CK1δ inhibition with gemcitabine holds promise as a future therapeutic option for metastatic pancreatic cancer as well as other cancers. Citation Format: Simon Bayle, Francesca Vena, Andrii Monastyrskyi, William Roush, Derek Duckett. New strategy to sensitize pancreatic and bladder cancer to gemcitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 950.