EGFR-TKI小分子標靶藥物治療非小細胞肺癌之細胞反應與藥物交互作用

The Study of NSCLC Cell Response and the Drug-Drug Interaction upon EGFR-TKI Small Molecular Treatment

王祥宇

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

交通大學分子醫學與生物工程研究所學位論文

2017年

博士

曾慶平;徐祖安

繁體中文

愈來愈高的癌症發生率是當前醫學重要的課題，過去使用化學治療藥物常因為嚴重的副作用而讓人聞之卻步，近十年來因為標靶藥物的發展讓癌症治療有更佳的選擇。其中在發生率近85%的非小細胞肺癌的治療中，因為亞洲人中有很高的EGFR突變機率而使肺癌標靶藥物發揮了重要的治療效果，但是幾乎無可避免的在標靶藥物治療一段時間後，皆因為產生抗藥性突變而失效。過去大多數針對肺癌標靶藥抗藥性的研究著墨於發生在癌細胞中的抗藥性突變或篩選出其他穩定的抗藥性機制，而很少關注EGFR-TKI標靶藥物對肺癌細胞產生的藥物影響與細胞對藥物產生的反應機制。生物遭遇壓力時的第一個反應是求生存，在治療過程中，藥物對癌細胞而言即是一個高度的壓力來源。所以本研究針對非小細胞肺癌細胞在EGFR-TKI標靶藥物出現時的細胞反應與藥物對細胞產生的藥物影響進行探討。有2個主要發現：1)非小細胞肺癌細胞在遭遇EGFR-TKI時能短暫的增加細胞貼附相關的應急反應，干擾細胞貼附應急反應會使得EGFR-TKI藥物的細胞毒殺效能提升；2)非小細胞肺癌細胞在遭遇EGFR-TKI時會出現類固醇合成功能下降，若以葡萄糖固醇類藥物干擾此現象時，會導致非小細胞肺癌細胞受EGFR-TKI藥物引起的細胞凋亡消失，並於小鼠模式證實EGFR-TKI藥物功能下降，且進一步在台灣健保資料庫臨床數據分析中見到合併使用產生較高的癌症惡化風險。 綜合上述結果，本研究透過研究肺癌細胞遭遇EGFR-TKI標靶藥物時的細胞反應變化，發現了能提高EGFR-TKI標靶藥物效能的藥物合併策略與臨床上可能的藥物交互作用，期望藉此能讓肺癌病患更受益於標靶藥物治療。

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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