ErbB4/KITENIN-Mediated Signaling is Activated in Cetuximab-Resistant Colorectal Cancer Cells
ErbB4/KITENIN signaling plays a role in epidermal growth factor receptor (EGFR)-independent EGF pathways mediating the invasiveness and tumorigenesis of colorectal cancer cells. However, whether alterations in ErbB4/KITENIN signaling play a role in the resistance to anti-EGFR therapy
remains unclear. Here, we established cetuximab-resistant DLD1 and HT29 cells, and analyzed changes in ErbB4/KITENIN signaling. c-Jun, a final effector in ErbB4/KITENIN-mediated signaling, was upregulated, whereas KITENIN levels remained constant in both cetuximab-resistant cell lines. The
phosphorylation of EGFR and ErbB4 was increased in cetuximab-resistant cells, suggesting that ErbB4/KITENIN signaling contributed to the acquisition of cetuximab resistance in the cells. Silencing of KITENIN and/or ErbB4 increased cetuximab sensitivity in cetuximab-resistant cells. This study
is the first to report the activation of ErbB4/KITENIN-mediated signaling in cetuximab-resistant colorectal cancer cells and the potential clinical application of ErbB4/KITENIN-targeting therapy for overcoming anti-EGFR resistance.
Keywords: Cetuximab; Colorectal Cancer; EGFR; ErbB4; KITENIN; Resistance
Document Type: Research Article
Affiliations: 1: College of Pharmacy, Sunchon National University, Sunchon, Jeonnam, 57922, Korea 2: Department of Environmental Engineering, Sunchon National University, Sunchon, Jeonnam, 57922, Korea 3: Department of Hematology-Oncology, Chonnam National University Medical School, Gwangju, 61469, Korea 4: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, 61469, Korea
Publication date: 01 February 2019
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