HDAC抑制劑克服非小細胞肺癌之 gefitinib抗藥性之研究

Abstract

非小細胞肺癌(NSCLC) 會表現過度活化之epidermal growth factor receptor (EGFR)，促進腫瘤形成。EGFR-tyrosine kinase inhibitors (EGFR-TKIs) 如gefitinib與erlotinib，能抑制過度活化之EGFR，使癌細胞無法增生及轉移，用於治療EGFR突變之非小細胞肺癌；然而TKI 治療後如產生EGFR 之T790M 突變或MET 之gene amplification，造成治療失敗，即為secondary resistance，而克服secondary resistance是非小細胞肺癌治療之關鍵問題。 在許多腫瘤中HDAC 有過度表現，而降低抑癌基因之表現，因此HDAC 為癌症治療之熱門標的，HDAC 抑制劑可經由調節染色質組蛋白及non-histone protein之乙醯化，誘發癌細胞死亡、凋亡及細胞週期停滯而有抗癌效果。 本實驗篩選出HDAC 抑制劑compound D，可抑制NSCLC 之細胞生長及減少EGFR 與MET 之表現。Compound D 與gefitinib 合併使用，對gefitinib 具抗藥性細胞之生長有加成性抑制作用，亦抑制其下游AKT 及ERK 之活化，並促進癌細胞凋亡。在動物模式中，併用compound D 與gefitinib 可顯著抑制腫瘤生長。因此，gefitinib 併用HDAC 抑制劑可克服gefitinib 之抗藥性，對於產生secondary resistance之NSCLC 病患是具潛力之治療策略。

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, which plays a pivotal role in cancer progression, is aberrantly overexpressed and abnormally activated in many cancers, such as non-small-cell lung cancer (NSCLC). EGFR-tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib have been shown to improve overall survival and approved for the treatment of EGFR-mutant NSCLC. Recently, it has been signified that primary and secondary resistance to EGFR-TKIs limits their clinical significance. For instance, T790M mutation in EGFR or c-MET gene amplification makes up most cases of secondary resistance. Targeting mutant EGFR or c-MET could overcome TKI resistance in NSCLC. In our study, combination of gefitinib with HDAC inhibitor compound D overcomes TKI resistance in NSCLC cell lines. Compound D down-regulated EGFR and MET, and then disturbed the phosphorylation of AKT and ERK in NSCLC. Combination of compound D and gefitinib showed a synergistic antiproliferative effect through decreasing the activities of AKT and ERK and increasing apoptotic cell death. In addition, the compound D/gefitinib combination potentially inhibited in vivo tumor growth. Our data suggest that the compound D/gefitinib combination represents a promising strategy to overcome EGFR-TKI resistance in NSCLC.