Targeting of beta 1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells

beta 1 Integrin-mediated cell-extracellular matrix interactions allow cancer cell survival and confer therapy resistance. It was shown that inhibition of beta 1 integrins sensitizes cells to radiotherapy. Here, we examined the impact of beta 1 integrin targeting on the repair of radiation-induced DNA double-strand breaks (DSBs). beta 1 Integrin inhibition was accomplished using the monoclonal antibody AIIB2 and experiments were performed in three-dimensional cell cultures and tumor xenografts of human head and neck squamous cell carcinoma (HNSCC) cell lines. AIIB2, X-ray irradiation, small interfering RNA-mediated knockdown and Olaparib treatment were performed and residual DSB number, protein and gene expression, non-homologous end joining (NHEJ) activity as well as clonogenic survival were determined. beta 1 Integrin targeting impaired repair of radiogenic DSB (gamma H2AX/53BP1, pDNA-PKcs T2609 foci) in vitro and in vivo and reduced the protein expression of Ku70, Rad50 and Nbs1. Further, we identified Ku70, Ku80 and DNA-PKcs but not poly(ADP-ribose) polymerase (PARP)-1 to reside in the beta 1 integrin pathway. Intriguingly, combined inhibition of beta 1 integrin and PARP using Olaparib was significantly more effective than either treatment alone in non-irradiated and irradiated HNSCC cells. Here, we support beta 1 integrins as potential cancer targets and highlight a regulatory role for beta 1 integrins in the repair of radiogenic DNA damage via classical NHEJ. Further, the data suggest combined targeting of beta 1 integrin and PARP as promising approach for radiosensitization of HNSCC.