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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Bromodomain and extra-terminal domain protein BRD4 is an oncogenic driver and therapeutic target in cancer.
• BRD4 inhibitors show moderate efficacy as monotherapy in preclinical cancer models.

Purpose of the Study:

• To identify synergistic drug combinations targeting head and neck squamous cell carcinoma (HNSCC).
• To investigate the therapeutic potential of combining BRD4 and CDK7 inhibition in HNSCC.

Main Methods:

• A drug synergy screen identified THZ1 (CDK7 inhibitor) as synergistic with JQ1 (BRD4 inhibitor) against HNSCC.
• Evaluated combinational effects on cell proliferation, apoptosis, and senescence in vitro.
• Assessed tumor growth inhibition in 4NQO-induced HNSCC and xenograft mouse models.
• Utilized RNA-sequencing to identify gene expression changes and performed mechanistic studies involving H3K27ac and YAP1.

Main Results:

• Combinational JQ1 and THZ1 treatment significantly impaired HNSCC cell proliferation, induced apoptosis and senescence.
• Dual BRD4 and CDK7 inhibition suppressed tumor growth and progression in preclinical HNSCC models.
• Mechanistically, the combination reduced H3K27ac enrichment at the YAP1 super-enhancer, inactivating its transcription and inducing anti-proliferative effects.
• Combined BRD4 and CDK7 upregulation correlated with poorer prognosis in HNSCC patients.

Conclusions:

• Pharmacological inhibition of both BRD4 and CDK7 represents a novel and effective therapeutic strategy for HNSCC.
• The synergistic combination overcomes limitations of monotherapy and targets key oncogenic pathways like YAP1.
• This approach holds significant potential for improving outcomes in head and neck cancer patients.