Interaction between epidermal growth factor receptor– and cyclooxygenase 2–mediated pathways and its implications for the chemoprevention of head and neck cancer

Abstract

Head and neck squamous cell carcinoma is a well-known model for chemoprevention studies because of its field cancerization effect, its multistep carcinogenesis process, and the easy accessibility of biopsies to target lesions. With new understandings of head and neck carcinogenesis and the development of molecular targeted therapy, chemoprevention trials for head and neck squamous cell carcinoma have been rapidly updated. Cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are gaining significant attention as potential chemopreventive agents. Both COX-2 and EGFR are involved in head and neck carcinogenesis. Targeting COX-2 and EGFR separately has shown promising antitumor activity. Recently, combinations of COX-2 and EGFR tyrosine kinase inhibitors have been reported to show synergistic/ additive effects in preclinical studies. Because COX-2 and EGFR tyrosine kinase inhibitors are toxic as single agents in clinical trials, the combination of COX-2 and EGFR tyrosine kinase inhibitors used at lower doses seems more promising than monotherapy with either as a novel strategy in head and neck cancer chemoprevention. [Mol Cancer Ther 2005;4(9):1448 -55]

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

“…Although numerous reports suggest that COX-2 and EGFR are closely related to each other and play an important role in tumor development (1,2,16,17,19,20), their exact mechanisms have not been well understood. PGE 2 , an end product of COX-2, is known to up-regulate EGFR activity through the E-prostanoid receptorcyclic AMP/protein kinase A-amphiregulin pathway or through an intracellular Src-mediated pathway independent of extracellular EGFR ligand release (1).…”

“…Although it has been verified that the actions of COX-2 and EGFR are closely related in cells, as described above, expression patterns of COX-2 and EGFR are highly variable among cancer cell types and frequently seem to be independent of each other. These facts suggest that COX-2 and EGFR may independently or complementarily function under particular circumstances according to cell specificity (1,20). Determining the precise type of relationship between the two proteins in a specific cancer type could provide useful clues for the development of new drugs or approaches (e.g., combined targeted strategies using COX-2-modulating and EGFR-modulating drugs for the treatment of cancer).…”

Oral-Specific Chemical Carcinogenesis in Mice: An Exciting Model for Cancer Prevention and Therapy

“…Czerninski et al's findings further support targeting the mTOR pathway as a chemoprevention strategy. Other potential targets for chemoprevention besides mTOR (18) include AKT (14,19,20), cyclooxygenase-2, and EGFR (21,22). The overexpression and activation of these molecules in precancerous lesions and tumors in this mouse model suggests its usefulness for evaluating new drugs that modulate these targets.…”

Arachidonic Acid Metabolism and Its Implication on Head and Neck Cancer

“…However, the signaling pathway involved in COX-2 via EGFR varies depending on the type of cells and inducers, but the ras/ raf/ mitogen-activated protein kinases (MAPKs) signaling pathways mainly contribute to both increased transcriptional and posttranscriptional controls. On the other hand, COX-2 could induce transactivation or upregulate EGFR expression (Choe et al, 2005;Husvik et al, 2009). …”