Tumor-penetrating peptide fused EGFR single-domain antibody enhances radiation responses following EGFR inhibition in gastric cancer

Abstract

Radiotherapy has been the primary method for the local control of several types of unresectable tumor, including gastric cancer. Patients with gastric cancer frequently express high levels of epidermal growth factor receptor (EGFR), which have been found to increase following radiotherapy treatment. This provides a basis for the combination of antibodies targeting EGFR and radiotherapy. In our previous study, a protein (anti-EGFR-iRGD) with bispecific targets and high permeability was constructed, and its effects on inhibiting the proliferation of gastric cancer cells was investigated. In the present study, the capacity of anti-EGFR-iRGD to modulate a radiation response was investigated and the specific mechanisms underlying these interactions were evaluated in gastric cancer cell lines and xenografts exhibiting high levels of EGFR. The radioenhancement of anti-EGFR-iRGD was associated with inhibited radiation-induced upregulation of EGFR, inhibited cell proliferation and promotion of cell apoptosis. In addition, anti-EGFR-iRGD appeared to permeate more into the tumor tissue following radiation. These findings indicated that the recombinant protein anti-EGFR-iRGD was a selective and effective radiosensitizer in EGFR-overexpressing gastric cancer cells and xenografts. These results further suggested that anti-EGFR-iRGD is a potential superior EGFR-targeted therapy combined with radiotherapy. Overall, the present study suggested that anti-EGFR-iRGD may be a promising candidate for preclinical and clinical use.