Combinational therapeutic targeting of BRD4 and CDK7 synergistically induces anticancer effects in head and neck squamous cell carcinoma.

Abstract

The bromodomain and extra-terminal domain protein BRD4 has been recognized as a key oncogenic driver and a druggable target against cancer. However, these BRD4 inhibitors as monotherapy were moderate in efficacy in preclinical models. Here we utilized a small-scale drug synergy screen that combined the BRD4 inhibitor (JQ1) with 8 epigenetic or transcriptional targeted chemicals and identified THZ1 (a CDK7 inhibitor) acting synergistically with JQ1 against head neck squamous cell carcinoma (HNSCC). Combinational JQ1 and THZ1 treatment impaired cell proliferation, induced apoptosis and senescence, which were largely recapitulated by dual BRD4 and CDK7 knockdown. Combinational treatment inhibited tumor growth and progression in 4NQO-induced HNSCC and xenograft animal models. RNA-sequencing analyses identified hundreds of differentially expressed genes modulated by JQ1 and THZ1, which were significantly enriched in categories including cell cycle and apoptosis. Mechanistically, combinational treatment reduced H3K27ac enrichment in the super-enhancer region of YAP1, which inactivated its transcription and in turn induced anti-proliferative and pro-apoptotic effects. Combined BRD4 and CDK7 upregulation associated with worst prognosis in HNSCC patients. Collectively, our findings reveal a novel therapeutic strategy of pharmacological inhibitions of BRD4 and CDK7 against HNSCC.

• Authors: Wei Zhang, Han Ge, Yue Jiang, Rong Huang, Yaping Wu, Dongmiao Wang, Songsong Guo, Sheng Li, Yanling Wang, Hongbing Jiang, Jie Cheng
• Journal: Cancer letters (Cancer Lett) Vol. 469 Pg. 510-523 (Jan 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 31765738 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• (+)-JQ1 compound
• Azepines
• BRD4 protein, human
• Cell Cycle Proteins
• Phenylenediamines
• Pyrimidines
• THZ1 compound
• Transcription Factors
• Triazoles
• Cyclin-Dependent Kinases
• Cyclin-Dependent Kinase-Activating Kinase

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Azepines (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors, genetics)
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinases (antagonists & inhibitors, genetics)
• Drug Synergism
• Humans
• Mice
• Phenylenediamines (pharmacology)
• Pyrimidines (pharmacology)
• Squamous Cell Carcinoma of Head and Neck (drug therapy, genetics, pathology)
• Transcription Factors (antagonists & inhibitors, genetics)
• Triazoles (pharmacology)
• Xenograft Model Antitumor Assays
• Cyclin-Dependent Kinase-Activating Kinase