HDAC6在非小細胞肺癌對EGFR-TKI抗藥性角色之研究

Abstract

表皮生長因子酪胺酸激酶抑制劑(EGFR-TKI)作為activating mutation非小細胞肺癌病人之一線用藥，初期能有效抑制腫瘤生長，但抗藥性終究會產生而導致腫瘤復發。本研究發現，第一代(HCC827/IR)及第三代(H1975/AR)抗藥性細胞株皆表現EMT及癌幹細胞之特性，且伴隨組蛋白去乙醯酶6(HDAC6)高度表現。HDAC6選擇性抑制劑ACY1215可反轉EMT並減少細胞遷移。ACY1215也能透過停滯細胞週期於S或是G2/M時期，進而誘發細胞凋亡、抑制群落形成。ACY1215與EGFR-TKI之加成藥效能克服對第一代抗藥性細胞及第三代抗藥性細胞產生之繼發性抗藥性。另一方面，引用shRNA 減弱HDAC6之表現，可降低波形蛋白(Vimentin)及ALDH1A1之表現。由於HCC827/IR不具有T790M突變、H1975/AR不具有C797S突變，說明HDAC6可能是導致非小細胞肺癌抗藥性之罪魁禍首。

As the first-line treatment for NSCLC patients with EGFR activating mutations, EGFR-TKIs effectively inhibit tumor progression but acquired resistance invariably develops. In this study, we found that both gefitinib-resistant (HCC827/IR) and AZD9291-resistant (H1975/AR) cells expressed characteristics of EMT and CSC, along with HDAC6 overexpression. A selective HDAC6 inhibitor-ACY1215 not only reversed EMT but also reduced cell migration. Meanwhile, ACY1215 could trigger apoptosis through cell cycle arrest at S or G2/M phase and further inhibited colony formation. Synergistic interaction between ACY1215 and EGFR-TKIs overcame the acquired resistance in both HCC827/IR and H1975/AR. On the other hand, knockdown of HDAC6 down-regulated the protein level of Vimentin and ALDH1A1. Since HCC827/IR and H1975/AR did not harbor T790M and C797S respectively, these results demonstrated that HDAC6 might be the culprit to confer EGFR-independent resistance in NSCLC.