The following is a summary of “EpEX, the soluble extracellular domain of EpCAM, resists cetuximab treatment of EGFR-high head and neck squamous cell carcinoma,” published in the July 2023 issue of Oral Oncology by Umemori et al.

Cetuximab (Cmab) is a molecularly targeted monoclonal antibody drug for treating head and neck squamous cell carcinoma (HNSC), even though cetuximab resistance is a significant problem. Epithelial cell adhesion molecule (EpCAM) is a well-established marker for numerous epithelial malignancies, whereas the soluble EpCAM extracellular domain (EpEX) is a ligand for epidermal growth factor receptor (EGFR). The researchers examined the expression of EpCAM in HNSC, its role in Cmab action, and the mechanism by which soluble EpEX activated EGFR and played critical roles in Cmab resistance. 

They first investigated the expression of EPCAM in HNSCs and its clinical significance using gene expression array databases. The effects of soluble EpEX and Cmab on intracellular signaling and Cmab efficacy in HNSC cell lines (HSC-3 and SAS) were then evaluated. The expression of EPCAM was found to be elevated in HNSC tumor tissues relative to normal tissues, and this elevation was associated with stage progression and prognosis. HNSC cells treated with soluble EpEX exhibited activation of the EGFR-ERK signaling pathway and nuclear translocation of EpCAM intracellular domains (EpICDs). 

EpEX resisted the antitumor effect of Cmab in a manner dependent on EGFR expression. Activation of EGFR by soluble EpEX increases Cmab resistance in HNSC cells. The EGFR-ERK signaling pathway and the EpCAM cleavage-induced nuclear translocation of EpICD may mediate epEX-induced Cmab resistance in HNSC. High EpCAM expression and cleavage are potential biomarkers for predicting Cmab’s clinical efficacy and resistance.

Source: sciencedirect.com/science/article/pii/S136883752300129X