The Study of NSCLC Cell Response and the Drug-Drug Interaction upon EGFR-TKI Small Molecular Treatment
Hsu, John T. -A.
|關鍵字:||標靶藥;肺癌;葡萄糖皮質醇;藥物交互作用;健保資料庫;抗藥性;EGFR-TKI;lung cancer;glucocorticoid;drug-drug interaction;NHIRD;drug resistance|
The increasing incidence of cancer attracts more and more attention in medical research. In recent years, targeting therapeutics have shown promising efficacy in a variety of cancers. Lung cancer is the leading cause of cancer death in the world, and approximate 85% is of non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) such as gefitinib, afatinib, and osimertinib have shown remarkable benefits in all stages of NSCLC patients harboring drug-sensitive mutations in the EGFR gene. In East Asian population, more than 50% NSCLC patients have such mutations. Unfortunately, almost all patients who initially responded to the EGFR-TKIs treatment eventually developed resistance to these target therapeutics. Several in vitro cell culture methods have been developed to study drug resistance mechanisms using cells obtained by prolonged drug treatment. However, relatively little is known how cancer cells would respond immediately upon EGFR targeting drugs. From the standpoints of cancer cells, striving to survive is the first priority when encountering anti-cancer drugs; and, we may hypothesis that cancer cell would use the cell emergency responses to defend drugs in some manners. This study focused on how the lung cancer cells respond upon EGFR-TKIs treatment and the consequence of interfering these cellular responses. There are two major findings in this study. First, emergency adhesion response occurred in NSCLC cells upon EGFR-TKI drug treatment, and the drug efficacy could be increased by interfering the cell emergency adhesion response. Second, an EGFR-TKI-induced downregulation of steroid biosynthesis pathway was identified. After this steroid biosynthesis pathway was reversed by glucocorticoids, the EGFR-TKI drug-induced cell apoptosis was totally abolished in cell-based and in vivo animal tests. These laboratory studies were translated into clinical application and a surprisingly increased risk of disease progression was observed in lung cancer patients receiving concomitant use of gefetinib and glucocorticoids (GCs) from a retrospective study employing Taiwan National Health Insurance Research Database. In conclusion, we found that drug induced cell responses were important to the application of EGFR-targeting therapy. Findings from this study may be translated into clinical applications to enhance the efficacy of EGFR-TKI therapy by simultaneously interfering cell emergency adhesion response. In addition, the unnecessary compromising effects caused by GCs use in TKI therapy may be minimized by awareness of such a potential effect.
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