β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy

Integrin signaling critically contributes to the progression, growth, and therapy resistance of malignant tumors. Here, we show that targeting of beta(1) integrins with inhibitory antibodies enhances the sensitivity to ionizing radiation and delays the growth of human head and neck squamous cell carcinoma cell lines in 3D cell culture and in xenograftecl mice. Mechanistically, dephosphorylation of focal adhesion kinase (FAK) upon inhibition of beta(1) integrin resulted in dissociation of a FAK/cortactin protein complex. This, in turn, downregutatted JNK signaling and induced cell rounding, leading to radiosensitization. Thus, these findings suggest that robust and selective pharmacological targeting of beta(1) integrins may provide therapeutic benefit to overcome tumor cell resistance to radiotherapy.