隨著上皮增生因子(epidermal growth factor receptor, EGFR)受器的tyrosine kinase inhibitor (TKI)的發展，此藥物在非小細胞肺癌開啟了治療的新章。然而這令人印象深刻的藥物最終卻會因癌細胞的抗性產生而失效，之後的治療則未有定論。為了研究癌細胞對TKI產生抗性的機制，我們針對EGFR基因的過量轉譯作研究。在前導實驗中我們發現在非小細胞肺癌細胞株A549中，將芳香烴受體核轉位蛋白(aryl hydrocarbon receptor nuclear translocator，Arnt，or hypoxia inducible factor 1-β)抑制後可以減少EGFR的表現。一系列的後續實驗卻發現在其他肺癌細胞株中並無如此的現象。我們另外針對另一個調控EGFR的蛋白質第二型環氧化酶(cyclooxygenase, COX-2)去設計Arnt的調節實驗。相較於子宮頸癌細胞株A431，SiHa，及口腔癌細胞株OEC-M1，在非小細胞肺癌細胞株H157中，Arnt的抑制卻無法使COX-2的表現減少。這也表現出這條調節路徑的複雜性。為了要辨認出Arnt及COX-2的臨床意義，我們將對gefitinib (一種TKI)產生抗性後使用過celecoxib (COX-2的抑制劑)的病人其臨床資料做統計，並且針對其檢體作免疫組織化學染色(IHC)。結果無論是Arnt或COX-2的IHC染色是否陽性並無法預測合併治療的藥效及生存時間是否獲得改善。然而更深入的分析卻發現，在整體生存時間來說，celecoxib用在COX-2 IHC陽性的病人中，可以改善COX-2表現所帶來不好的預後影響。結論為造成EGFR抑制劑抗性的訊息傳遞路線是很複雜的，在Arnt，COX-2及EGFR間的交叉關係之外應有別的物質參入調控。另外在臨床上考慮到最佳的益處時，在已產生gefitinib抗性的病人中，若其IHC為陽性表現，可以考慮加入COX-2抑制劑來作拯救性的治療。

The development of tyrosine kinase inhibitors (TKI) targeting epidermal growth factor receptor (EGFR) has brought the treatment of non-small cell lung cancer (NSCLC) to a new era. The impressive therapy, however, leads to the development of drug resistance eventually, and further management is a conflict. To study the resistance of TKI, we investigated the factor that is to up-regulate the transcription of EGFR gene. In our preliminary data, since EGFR was down-regulated by knocking down aryl hydrocarbon receptor nuclear translocator (Arnt, or hypoxia inducible factor 1-β) in NSCLC cell line A549, a series of study was designed. The phenomenon, however, was not proved in the other NSCLC cell lines. In addition, we also investigated Arnt to regulate cyclooxygenase-2 (COX-2) expression, which is also a factor that up-regulates EGFR when over-expressed. Unlike cervical cancer cell lines A431, SiHa, and oral cancer cell line OEC-M1, knocking down Arnt in NSCLC cell line H157 did not successfully modulate the expression of COX-2, implying the potentially complicated network of the regulating system. In order to investigate the impact of Arnt and COX-2 in clinical practice, we arranged an observational study of immunohistochmistry (IHC) analyses on the patients who had received celecoxib, a specific COX-2 inhibitor, after tumor progression while taking gefitinib, an EGFR-TKI. The result showed neither positive staining of Arnt nor COX-2 was able to predict the response or the survival benefit of adding celecoxib to reverse the resistance of gefitinb. Nevertheless, further analysis revealed that celecoxib improved the overall survival time of the subgroup with positive COX-2 IHC staining, implying the drug to minimize the dismal effect of COX-2 expression. In conclusion, the signal pathways involving the resistance of EGFR inhibitor is complicate, and more elements is involved in the crosstalk among Arnt, COX-2 and EGFR network. Considering the benefit, adding COX-2 inhibitor to the patients with positive COX-2 IHC staining may be the best strategy in the patients that have developed resistance to gefitinib for salvage therapy.

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