Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab

• Published in: PloS one Vol. 12; no. 12; p. e0188932
• Main Authors: Sun, Chaonan, Han, Chuyang, Jiang, Yuanjun, Han, Ning, Zhang, Miao, Li, Guang, Qiao, Qiao
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.12.2017; Public Library of Science (PLoS)
• Subjects: Activating Transcription Factor 6 - metabolism; Apoptosis; Autophagy; Biology and life sciences; Cancer therapies; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell cycle; Cell death; Cell Line, Tumor; Cetuximab; Cetuximab - pharmacology; Chemotherapy; Complications and side effects; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; Dosage and administration; Double-strand break repair; Drug resistance; Drug therapy; Drugs; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endoribonucleases - metabolism; Epidermal growth factor receptors; Gene expression; Genetic aspects; Head & neck cancer; Heat-Shock Proteins - antagonists & inhibitors; Humans; Immunohistochemistry; Immunotherapy; Inhibition; Kinases; Lung cancer; Medical prognosis; Medicine and Health Sciences; Monoclonal antibodies; Oropharyngeal Neoplasms - metabolism; Oropharyngeal Neoplasms - pathology; Patients; Phagocytosis; Pharyngeal cancer; Physiological aspects; Protein-Serine-Threonine Kinases - metabolism; Proteins; Radiation; Radiation damage; Radiation effects; Radiation therapy; Radiation tolerance; Radiation Tolerance - drug effects; Radioresistance; Radiosensitivity; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Repair; Research and Analysis Methods; Signal Transduction; Signaling; Synergistic effect; Targeted cancer therapy; Throat cancer; Tumors; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0188932

The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB) repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05). Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.