Renal cell carcinoma (RCC) is a major cancer of the kidney. The 5-year survival rate is overall 74% and only 8% for Stage 4 cancers. Several agents including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors are available as first- or second-line therapy for metastatic RCC.
However, the survival benefits are limited. Recently, THZ1 has been identified as a cyclin-dependent kinase 7 (CDK7) inhibitor that interferes with the transcriptional machinery. Although it is apparently effective in various cancer models, the data for RCC has never been reported. In this study, we demonstrated the impact of CDK7 expression on tumor progression and patient survival in a clinical cohort. We found that THZ1 induced apoptosis and cell cycle arrest in RCC cells, thereby reducing cell viability. Furthermore, THZ1 acted synergistically with temsirolimus in vitro, probably by inhibiting autophagy. Moreover, compared to either THZ1 or temsirolimus used individually, the combination treatment further suppressed tumor growth in vivo. These results indicate that CDK7 is associated with the progression and prognosis of RCC, and is a potential therapeutic target for overcoming drug resistance in this cancer.
Cancer letters. 2019 Dec 06 [Epub ahead of print]
Po-Ming Chow, Shing-Hwa Liu, Yu-Wei Chang, Kuan-Lin Kuo, Wei-Chou Lin, Kuo-How Huang
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan; Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: ., Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipe, 100, Taiwan. Electronic address: ., Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: ., Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan; Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: ., Department of Pathology, National Taiwan University Hospital, Taipe, 100, Taiwan. Electronic address: ., Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/31812697