Erk1/2-Dependent HNSCC Cell Susceptibility to Erastin-Induced Ferroptosis

Unfavorable clinical outcomes highlight the need for cancer researchers to develop novel therapeutic strategies to combat therapeutic resistance in patients with head and neck squamous cell carcinoma (HNSCC). Recently, ferroptosis has emerged as a promising pathway with druggable targets, such as xCT (SLC7A11). However, the molecular mechanisms that determine the susceptibility of HNSCC cells to ferroptosis remain poorly understood.

This study aimed to investigate whether HNSCC cells with activated Erk1/2 are more vulnerable to ferroptosis induction. Our findings revealed that xCT (SLC7A11) was overexpressed in malignant tissues from HNSCC patients, while normal mucosa exhibited only weak expression of the protein. To assess the role of Erk1/2 in cell viability reduction caused by erastin, we utilized xCT-overexpressing FaDu and SCC25 HNSCC cell lines. Inhibition of Erk1/2 signaling using ravoxertinib decreased the efficacy of erastin by affecting reactive oxygen species (ROS) production and increasing the expression of ROS scavengers SOD1 and SOD2, which ultimately suppressed lipid peroxidation.

Thus, our results suggest that erastin-induced ferroptosis is a promising strategy that could be further developed for treating HNSCC. Since the induction of ferroptosis via erastin is closely tied to Erk1/2 expression, this MAP kinase may serve as a predictive marker for the response of cancer cells to erastin GDC-0994 treatment.