Inhibition of autophagy increases head and neck cancer sensitivity to cetuximab and radiation therapy.

The five-year survival rate of head and neck squamous cell carcinoma (HNSCC) remains around 50% despite advances in treatments over the last 20 years. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), demonstrates limited efficacy both alone and in combination with chemotherapy, with response rates below 20% and 35%, respectively. This underscores the critical need for novel therapeutic strategies and a better understanding of treatment resistance mechanisms in HNSCC. Autophagy, a cell survival process essential to cellular stress for both normal and cancer cells, may contribute to therapeutic resistance in HNSCC. We hypothesized that current treatments might inadvertently activate autophagy, enabling tumor cells to evade cell death. We demonstrated that basal autophagy is elevated in cetuximab-resistant cells using an isogenic pair of cetuximab-sensitive and -resistant cell lines. Furthermore, combining cetuximab or radiation therapy with SAR405, an autophagy inhibitor, significantly enhanced growth inhibition both in vitro and in vivo compared to either treatment alone. Knockdown of LAPTM4B or EGFR significantly reduced cetuximab-induced autophagy. In contrast, radiation-induced autophagy is primarily driven by mitochondrial autophagy (mitophagy). Diminished radiation-induced autophagy was observed by the knockdown of PINK1, a key regulator of mitophagy. These findings highlight that inhibition of autophagy can improve the efficacy of HNSCC treatments and suggest that targeting specific autophagy subtypes may be crucial for developing personalized treatment combinations for HNSCC patients.