高表現FOXC1在非小細胞肺癌對EGFR—TKI抗藥性之研究

Abstract

以EGFR-TKI治療EGFR activating mutation之非小細胞肺癌病人，具相當好的療效，但數個月後病人會產生acquired resistance。轉錄因子FOXC1在癌症中扮演重要角色，我們發現，在EGFR-TKI抗藥性細胞中，其表現增加。本篇論文使用H1975與H1975/AR (AZD9291 resistance) 細胞探討FOXC1在EGFR-TKI抗藥性之角色。 過量表現FOXC1於H1975細胞，可增進細胞之生長速度、遷移能力與形成球體（sphere）癌幹細胞，FOXC1亦調控癌幹細胞基因ALDH1A1之表現。在H1975/AR細胞抑制FOXC1之表現會促進RhoGDI2轉錄；在H1975細胞抑制RhoGDI2，會促進細胞之遷移能力與癌幹細胞特性。因此ALDH1A1與RhoGDI2可能均為FOXC1之下游標的。在原位肺癌動物模式發現，高表現FOXC1可促進腫瘤生長；以Kaplan Meier Plotter分析，FOXC1高表現之肺腺癌病人整體存活率較差。這些發現推測FOXC1可能與EGFR-TKI之抗藥性有關，可成為治療非小細胞肺癌的一個預後標記。

EGFR tyrosine kinase inhibitors (EGFR-TKIs) have shown good efficacy in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, acquired resistance develops after several months of treatment. Forkhead Box C1 (FOXC1) is an important transcriptional regulator associated with a wide variety of carcinomas including NSCLC. In this study, we found the overexpression of FOXC1 in EGFR-TKI resistant cells. Its role in the resistance of EGFR-TKIs was investigated using H1975 and AZD9291-resistant H1975/AR cell lines. Overexpression of FOXC1 in H1975 cells led to an increase in cell proliferation, migration and sphere-forming ability. In addition, FOXC1-overexpressing cells showed an up-regulation of ALDH1A1. On the other hand, knockdown of FOXC1 in H1975/AR cells showed an up-regulation of RhoGDI2. Further analysis demonstrated that knockdown of RhoGDI2 in H1975 cells increased cell migration and sphere-forming ability. Therefore ALDH1A1 and RhoGDI2 might be the downstream targets of FOXC1. Furthermore, overexpression of FOXC1 increased tumor growth in orthotopic lung cancer model. In Kaplan Meier Plotter database, high expression of FOXC1 is related to poor overall survival in lung adenocarcinoma. These findings indicate that FOXC1 might involve in the resistance of EGFR-TKIs and provide a possible prognostic marker for the treatment of NSCLC.