The Covalent CDK7 Inhibitor THZ1 Enhances Temsirolimus-Induced Cytotoxicity via Autophagy Suppression in Human Renal Cell Carcinoma - Beyond the Abstract

The purpose of this study was to find a new potential therapy for renal cell carcinoma (RCC) since the 5-year overall survival rate for stage 3 and 4 cancers are 53% and 8%, respectively. Although there are some treatments for metastatic RCC, the survival benefits are limited.

In our clinical data, we found that the expression of CDK7 was significantly higher in the advanced-stage tumors. Besides, the overall survival was significantly shorter in patients with higher CDK7 expression in the tumors. These results suggest that CDK7 may be a potential target for overcoming RCC.

We then further demonstrated that THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), has the ability to cause cell death through inducing apoptosis and cell cycle arrest in RCC cells. The results also show that targeting CDK7 suppresses temsirolimus-induced autophagy, a mechanism underlying resistance to temsirolimus. Moreover, we found that the combination treatment with THZ1 and temsirolimus further suppressed tumor growth in mice xenografts models.

In conclusion, this research not only clarifies that CDK7 is associated with the progression and prognosis of RCC, but provides a potential therapeutic manner by targeting CDK7 with THZ1 for overcoming drug resistance in RCC.

Written by: Yu-Wei Chang, and Po-Ming Chow, MD, Department of Urology, National Taiwan University Hospital, Taipei, Taiwan

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