Journal
HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK
Volume 43, Issue 11, Pages 3364-3373Publisher
WILEY
DOI: 10.1002/hed.26827
Keywords
BET; BRD2; cetuximab resistance; PD-L1 upregulation
Categories
Funding
- National Cancer Institute [R35CA231998, U54CA209891]
- National Institute of Dental and Craniofacial Research [T32DE007306]
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The study found that PD-L1 expression is significantly elevated in HNSCC cell line models resistant to targeted antibodies, and this expression is regulated by BET proteins. Treatment with BET inhibitor JQ1, BET PROTAC MZ1, or RNAi-mediated knockdown of BRD2 can reduce PD-L1 expression.
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.
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