PD‐L1 is upregulated via BRD2 in head and neck squamous cell carcinoma models of acquired cetuximab resistance

Abstract Background Tumor models resistant to EGFR tyrosine kinase inhibitors or cisplatin express higher levels of the immune checkpoint molecule PD‐L1. We sought to determine whether PD‐L1 expression is elevated in head and neck squamous cell carcinoma (HNSCC) models of acquired cetuximab resistance and whether the expression is regulated by bromodomain and extraterminal domain (BET) proteins. Methods Expression of PD‐L1 was assessed in HNSCC cell line models of acquired cetuximab resistance. Proteolysis targeting chimera (PROTAC)‐ and RNAi‐mediated targeting were used to assess the role of BET proteins. Results Cetuximab‐resistant HNSCC cells expressed elevated PD‐L1 compared to cetuximab‐sensitive controls. Treatment with the BET inhibitor JQ1, the BET PROTAC MZ1, or RNAi‐mediated knockdown of BRD2 decreased PD‐L1 expression. Knockdown of BRD2 also reduced the elevated levels of PD‐L1 seen in a model of acquired cisplatin resistance. Conclusions PD‐L1 is significantly elevated in HNSCC models of acquired cetuximab and cisplatin resistance where BRD2 is the primary regulator.