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.

• Authors: Neil E Bhola, Christian Njatcha, Lanlin Hu, Eliot D Lee, Jamie V Shiah, Mi-Ok Kim, Daniel E Johnson, Jennifer R Grandis
• Journal: Head & neck (Head Neck) Vol. 43 Issue 11 Pg. 3364-3373 (11 2021) ISSN: 1097-0347 [Electronic] United States
• PMID: 34346116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021 Wiley Periodicals LLC.

Chemical References

• B7-H1 Antigen
• BRD2 protein, human
• CD274 protein, human
• Transcription Factors
• Cetuximab

Topics

• B7-H1 Antigen (genetics)
• Cell Line, Tumor
• Cetuximab (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Head and Neck Neoplasms (drug therapy, genetics)
• Humans
• Squamous Cell Carcinoma of Head and Neck (drug therapy, genetics)
• Transcription Factors