The role of Lymphotoxin-β in Cetuximab resistance of head and neck cancer

• Main Authors: Yang-Hui Ho, 何仰惠
• Other Authors: Muh-Hwa Yang
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/2f2vb3

碩士 === 國立陽明大學 === 臨床醫學研究所 === 103 === Cetuximab, a monoclonal antibody against the epidermal growth factor receptor EGFR extracellular domain, has been approved for the treatment of head and neck squamous cell carcinomas (HNSCC). However, many patients acquire resistance after Cetuximab treatment. To clarify the reason of resistance response in HNSCC, we established Cetuximab-resistant cell line in vitro. By RNA-sequencing, we found Snail and Lymphotoxin beta (LTβ) highly expressed in Cetuximab-resistant cell line. Our previously results indicated Snail, an important inducer of epithelial-mesenchymal transtition (EMT), regulates cytokines expression in cancer cells, such as LTβ. Other studies indicated that cancer cells acquire drug resistance in the process of EMT. Therefore, we proposed Snail- LTβ axis drives Cetuximab resistance. Our results showed knock-down of Snail or LTβ increased cytotoxic effect of Cetuximab in resistance cells. It demonstrated Snail- LTβ axis plays a major role in Cetuximab resistance of HNSCC. However, the function of LTβ in cancer cell remains elusive. Previous studies show LTβ bind lymphotoxin-alpha to form heterotrimer- LTα1β2 on dendritic cell surface then bind to LTβ receptor in other cells which activated NFKB pathway. Our data found that Cetuximab resistance cells expressed higher NFKB downstream genes than wild-type cancer cells. We thought NFκB signaling is important for HNSCC acquired Cetuximab-resistant. We combined NFκB inhibitor and Cetuximab treatment showed great synergistic effect for Cetuximab-resistant cells. Taken together, this study presents a therapeutic option by enhancing Cetuximab effectiveness for Cetuximab-resistant patients.