Targeting human epidermal growth factor receptor 2 enhances radiosensitivity and reduces the metastatic potential of Lewis lung carcinoma cells

• Published in: Radiation oncology (London, England) England), 2020-03, Vol.15 (1), p.58-11, Article 58
• Main Authors: Tien, Yun, Tsai, Chiao-Ling, Hou, Wei-Hsien, Chiang, Yun, Hsu, Feng-Ming, Tsai, Yu-Chieh, Cheng, Jason Chia-Hsien
• Format: Article
• Language: English
• Subjects: Afatinib; Afatinib - pharmacology; Animals; Cancer therapies; Carcinoma, Lewis Lung - pathology; Carcinoma, Lewis Lung - radiotherapy; Care and treatment; Cell Line, Tumor; Development and progression; Epidermal growth factor; ErbB Receptors - antagonists & inhibitors; Experiments; Gene expression; Genetic aspects; Growth factors; Health aspects; Human epidermal growth factor receptor 2; Humans; Immunoglobulins; Innovations; Kinases; Lung cancer; Lung carcinoma; Male; Matrix Metalloproteinase 9 - physiology; Medical prognosis; Metastases; Metastasis; Mice; Mice, Inbred C57BL; MMP-9; Molecular targeted therapy; Mutants; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Protein expression; Proteins; Radiation; Radiation Tolerance - drug effects; Radiosensitivity; Radiotherapy; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - physiology; Signal Transduction; Tumors
• ISSN: 1748-717X; 1748-717X
• DOI: 10.1186/s13014-020-01493-8

Sublethal radiation induces matrix metalloproteinase 9 (MMP-9)-mediated radioresistance in Lewis lung carcinoma (LLC) cells and their metastatic dissemination. We aim to determine if EGFR/HER2 activation associates with MMP-9-mediated radioresistance and invasiveness in irradiated LLC cells. LLC cells were treated with erlotinib or afatinib followed by sublethal radiation. After irradiation, we examined the phosphorylation of EGFR/HER2 and MMP-9 expression. Colony formation assay determined if the kinase inhibitors sensitize LLC cells to radiation. Matrigel-coated Boyden chamber assay assessed cellular invasiveness. Resulting tumors of wild-type LLC cells or HER2 knock-down mutant cells were irradiated to induce pulmonary metastases. Afatinib more effectively sensitized LLC cells to radiation and decreased invasiveness by inhibiting phosphorylation of EGFR, HER2, Akt, ERK, and p38, and down-regulating MMP-9 when compared to erlotinib. Afatinib abolished radiation-induced lung metastases in vivo. Furthermore, LLC HER2 knock-down cells treated with radiation had growth inhibition. Dual inhibition of radiation-activated EGFR and HER2 signaling by afatinib suppressed the proliferation and invasion of irradiated LLC cells. Increased radiosensitivity and decreased metastatic dissemination were observed by pharmacological or genetic HER2 inhibition in vivo. These findings indicate that HER2 plays a pivotal role in enhancing radioresistance and reducing metastatic potential of LLC cells.