Abstract
Bladder cancer is the second most common genitourinary malignancy in the world. However, only immune-checkpoint inhibitors and erdafitinib are available to treat advanced bladder cancer. Our previous study reported that 4-((4-(4-ethylpiperazin-1-yl) phenyl)amino)-N-(3,4,5-trichlorophenyl)-7H-pyrrolo-[2, 3-d]pyrimidine-7-carboxamide hydrochloride (13i HCl) is a potent CK1δ inhibitor showing significant anti-bladder cancer activity. In this study, we elucidated the pharmacological mechanisms underlying 13i HCl’s inhibition of human bladder cancer. Our results demonstrate that expression of the CSNK1D gene, which codes for CK1δ, is upregulated in superficial and infiltrating bladder cancer patients in two independent datasets. CK1δ knockdown decreased β-catenin expression in bladder cancer cells and inhibited their growth. Additionally, 13i HCl suppressed bladder cancer cell proliferation and increased apoptosis. We also observed that inhibition of CK1δ using 13i HCl or PF-670462 triggers necroptosis in bladder cancer cells. Finally, 13i HCl inhibited bladder cancer cell migration and reversed their mesenchymal characteristics. These findings suggest further development of 13i HCl as a potential therapeutic agent to treat bladder cancer is warranted.
Highlights
Bladder cancer is the second most common genitourinary malignancy in the world, with an estimated 549,393 new cases and 199,922 deaths in 2018 [1]
The results demonstrated that the gene expression of CSNK1D was upregulated in superficial and infiltrating bladder cancer patients (Figure 1A, 1B)
We examined CK1δ protein levels in different bladder cancer cell lines, and found that RT112 and T24 express the highest levels of CK1δ (Figure 1C)
Summary
Bladder cancer is the second most common genitourinary malignancy in the world, with an estimated 549,393 new cases and 199,922 deaths in 2018 [1]. 70% of patients are newly diagnosed with non-muscle invasive bladder cancers (NMIBC), which have a five-year survival rate of ~90%. NMIBCs have a high recurrence rate and a high probability of progressing toward muscle invasive bladder cancers (MIBCs) [3], with a dramatically reduced five-year survival rate once the disease becomes metastatic [4], since treatment for metastatic bladder cancer has seen little progress in decades [3]. Patients who received platinum-based chemotherapy have an overall survival rate of 9-15 months. A pan-FGFR inhibitor, has been recently approved as a monotherapy option for patients www.aging-us.com with locally-advanced or metastatic urothelial cancer [9], caring for bladder cancer patients remains a huge social problem due to the high economic burden from end-of-life care, high recurrence rate of NMIBCs, and lack of effective treatments [10]. There is an unmet need to develop novel therapeutic agents for advanced bladder cancer patients
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