THZ531 and Thyroid-Neoplasms

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC.

Topics: Anilides; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinases; DNA Repair; Down-Regulation; Doxorubicin; Drug Synergism; Gene Expression Regulation; Humans; Nuclear Proteins; Oncogenes; Protein Kinase Inhibitors; Pyrimidines; ran GTP-Binding Protein; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transcription, Genetic