CDK7 inhibition by THZ1 suppresses cancer stemness in both chemonaïve and chemoresistant urothelial carcinoma via the hedgehog signaling pathway. (1st June 2021)

• Record Type: Journal Article
• Authors: Chow, Po-Ming; Chang, Yu-Wei; Kuo, Kuan-Lin; Lin, Wei-Chou; Liu, Shing-Hwa; Huang, Kuo-How
• Is Part Of: Cancer letters. Volume 507(2021)
• Page Start: 70
• Page End: 79
• Publication Date: 2021-06-01
• Subjects: Bladder cancer -- Cisplatin -- Drug resistance -- Cancer stem cell -- Apoptosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.03.012
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Urothelial carcinoma (UC) is the most common type of bladder cancer, with a 5-year survival rate of only 4.6% in metastatic UC. Despite the advances related to immune-checkpoint inhibitor therapy, chemotherapy remains the standard of care for metastatic diseases, with a 50% response rate. The covalent cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 interferes with transcription machinery and is reported to be effective in cancers without targetable mutations. Therefore, we investigated the therapeutic effect of THZ1 on UC and examined possible mechanisms underlying its effects in both chemonaïve and chemosensitive cancers. CDK7 expression is increased in bladder cancer tissues, especially in patients with chemoresistance. THZ1 induced apoptosis and decreased viability in RT4, BFTC905, HT1376, T24, and T24/R UC cell lines. RNA-sequencing, immunoblotting, and sphere-formation assays confirmed that THZ1 suppressed cancer stemness. In the mouse xenograft model, THZ1 suppressed both chemonaïve and chemoresistant tumors. These results indicate that CDK7 inhibition-related cancer stemness suppression is a potential therapeutic strategy for both chemonaïve and chemoresistant UC. Highlights: THZ1 is effective against both chemonaïve and chemoresistant cancers. CDK7 may play an important role in cancer stemness. CDK7 inhibition suppresses cancer stemness via the hedgehog signaling pathway. CDK7 is a potential therapeutic target for chemoresistant urothelial carcinoma.