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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.