In this study, we characterize the biologically- and clinically aggressive phenotype driven by METN375S in LUSC and HNSCC, elucidate the intriguing mechanism by which METN375S co-opts HER2 signaling to drive SCCs, and crucially, translate our findings into therapeutically cogent interventions with the successful therapy of tumor-bearing animals using commercially-available HER2 inhibitors. Here, ERBB2 is linked to head and neck squamous cell carcinoma.