The covalent CDK7 inhibitor THZ1 enhances temsirolimus-induced cytotoxicity via autophagy suppression in human renal cell carcinoma
Journal
Cancer Letters
Journal Volume
471
Pages
27-37
Date Issued
2020
Author(s)
Abstract
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. ? 2019 Elsevier B.V.
SDGs
Other Subjects
antineoplastic agent; cyclin dependent kinase 7; cyclin dependent kinase 7 inhibitor; cyclin dependent kinase inhibitor; temsirolimus; thz 1; unclassified drug; antineoplastic agent; cyclin dependent kinase; cyclin-dependent kinase-activating kinase; phenylenediamine derivative; pyrimidine derivative; rapamycin; temsirolimus; THZ1 compound; animal experiment; animal model; antineoplastic activity; apoptosis; Article; autophagy; cancer combination chemotherapy; cancer inhibition; cancer patient; cancer prognosis; cell viability; cohort analysis; concentration response; controlled study; cytotoxicity; drug potentiation; drug targeting; female; G1 phase cell cycle checkpoint; human; human cell; human tissue; in vitro study; in vivo study; major clinical study; male; monotherapy; mouse; nonhuman; priority journal; protein expression; renal cell carcinoma; renal cell carcinoma cell line; animal; autophagy; biosynthesis; cancer staging; drug effect; drug potentiation; drug screening; enzymology; kidney tumor; nude mouse; pathology; randomization; renal cell carcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Carcinoma, Renal Cell; Cyclin-Dependent Kinases; Drug Synergism; Humans; Kidney Neoplasms; Mice; Mice, Nude; Neoplasm Staging; Phenylenediamines; Pyrimidines; Random Allocation; Sirolimus; Xenograft Model Antitumor Assays
Type
journal article