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Purpose: In head and neck squamous cell carcinoma (HNSCC), the incidence of RAS mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation–mediated de novo resistance. Here, we investigated the driver gene mutation–independent mechanism for cetuximab resistance in HNSCC.

Experimental Design: We used the in vitro-selected and in vivo-selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab. Zebrafish model was applied for evaluating the synergistic effect of combinatory drugs for overcoming cetuximab resistance.

Results: The cetuximab-resistant HNSCC cells undergo a Snail-induced epithelial–mesenchymal transition. Mechanistically …