According to data from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rates, 2000-2016, for invasive bladder cancer were approximately 70% for localized cancer, 35% for regional, and 6% for metastatic bladder cancer.
These rates have not changed significantly since the late 1980s, indicating a need for new treatments to improve patient survival rates. Given that in the United States alone, an estimated 80,470 people were expected to be diagnosed and 17,670 expected to die from it in 2019, there is a clear need for more effective treatments.
The serine/threonine kinase CK1δ gene is amplified in ~50% of bladder tumors, which correlates with enhanced CK1δ expression. The kinase phosphorylates several cancer relevant targets such as Wnt, p53, and the death-receptors FADD and BID, making CK1δ a potentially promising target for bladder cancer therapy.
Chun-Han Chen and colleagues from the Taipei Medical University, Taiwan, previously synthesized a pyrimidine derivative called 13i HCl that potently inhibits CK1δ. In a new study published in the journal Aging they determined its mechanism of action in bladder cancer.
When CK1δ was reduced at the RNA level in bladder cancer cell lines their viability was reduced. 13i HCl CK1δ inhibitor also reduced cell viability in a dose responsive manner. A non-cancer cell line was not affected to the same extent and the cancer cell lines.
Propidium iodide flow cytometry analysis indicated that the compound increased the proportion of sub-G1 (non-viable) cells in a time and dose dependent manner. Higher doses of 13i HCl clearly activated caspase-3, -8, -9 as well as PARP, indicated by mobility shift on Western blot, suggesting apoptosis. The results also indicated that CK1δ could trigger necroptosis or programmed necrosis, which importantly could have an immune system stimulating effect against the cancer.
Using in vitro wound healing assay, the authors showed that 13i HCl decreased the ability of bladder cancer cell lines to fill a lane cleared in the 2d cell monolayer in a dose responsive manner.
The present study was limited to 2D in vitro analysis and it will be important to see if the effects of 13i HCl remain the same in 3D models such as organoids and potentially organ-on-chip platforms. The authors mention that CK1δ is a potential target in central nervous system (CNS) diseases and these 3D platforms would also be useful for interrogating CK1δ in these diseases as well.
“These results suggest that CK1δ could be a valuable therapeutic target to treat advanced bladder cancer, and that further development of compound 13i HCl is warranted to improve patient outcomes,” concluded the authors.