BET inhibition overcomes receptor tyrosine kinase-mediated cetuximab resistance in HNSCC

Surrogate receptor tyrosine kinase (RTK) activation, such as HER3, MET, and AXL, is one of the major causes of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). Researchers have identified a protein that coregulates the expression of multiple RTKs and its potential to overcome cetuximab resistance as a molecular target. Studies have shown that bromodomain-containing protein-4 (BRD4) can regulate the expression of RTKs in breast cancer models under the background of PI3K and HER2 inhibition of drug resistance. The researchers hypothesized that BDR4 inhibition could overcome cetuximab resistance by inhibiting the expression of complementary RTK. RTK and BRD4 expression in HNSCC cell lines resistant to cetuximab showed that several RTKs, such as MET and AXL, were upregulated in the cetuximab-resistant clones, and the percentage of cells expressing BRD4 was increased. However, targeted inhibition of BRD4 resulted in the loss of cell viability, which was associated with decreased expression of alternative RTK. The combination of cetuximab and the bromodomain inhibitor JQ1 treatment downregulates RTK and overcomes cetuximab resistance in the HNSCC PDX model. These results suggest that cetuximab combined with bromine domain inhibition may provide a novel therapeutic strategy for HNSCC treatment.