YB-1在非小细胞肺癌EGFR-TKIs耐药中的作用及机制研究

TKI has shown excellent efficacy in targeted treatment of NSCLC with EGFR mutation, but the development of drug resistance becomes a new challenge in lung cancer treatment. YB-1 is highly expressed in many human tumors, and plays a critical role in drug resistance of tumors. However, up to now, the role of YB-1 in EGFR-TKIs resistance and the relative mechanism is still poorly understood. Our previous studis showed that knockdown YB-1 could increase the sensitivity to gefitinib in NSCLC cells. It indicated that YB-1 is involved in EGFR-TKIs resistance. On the basis of the previous study, we investigated the role of YB-1 in primary and acquired resistance of EGFR-TKIs. Subsequently, we chose Ras-Raf/MAPK and PI3K/Akt signaling pathway as the preferred objects to explore the mechanism of YB-1-mediated EGFR-TKIs resistance. Further, we determined the new target of YB-1 using chip-sequencing technology. Finally, we explored the role of YB-1 in EGFR-TKIs resistance and the relative mechanism by the establishment of animal model. This study may provide theoretical basis for pathogenesis of NSCLC and effective treatment of EGFR-TKIs, and provide new therapeutic target for NSCLC.

TKI靶向治疗EGFR基因突变晚期NSCLC疗效卓越，但随之出现的耐药成为肺癌治疗的新挑战。YB-1在人类多种肿瘤中高表达并且与肿瘤耐药密切相关。但目前有关YB-1在NSCLC EGFR-TKIs耐药中的作用机制尚不明确。申请者前期研究发现，敲低YB-1的表达可以增加NSCLC细胞对吉非替尼的敏感性，提示YB-1与EGFR-TKIs的耐药有关。本研究拟在前期工作基础上，明确YB-1在EGFR-TKIs原发耐药和继发耐药中的作用；以Ras-Raf/MAPK和PI3K/Akt信号通路为切入点，分析YB-1参与EGFR-TKIs耐药的分子机制；利用Chip-sequencing方法筛选YB-1调控的耐药相关的靶基因；通过动物模型的建立，从整体水平探讨YB-1在EGFR-TKIs耐药中的作用及机制。研究结果可为指导EGFR-TKIs有效治疗提供理论依据，为今后针对肺癌的基因治疗提供可能的新靶点。

表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）靶向治疗EGFR基因突变晚期非小细胞肺癌（NSCLC）疗效卓越, 但随之出现的耐药成为肺癌治疗的新挑战。YB-1 （Y box-binding protein-1）在人类多种肿瘤中高表达并且与肿瘤耐药密切相关。但目前有关YB-1在NSCLC EGFR-TKIs耐药中的作用机制尚不明确。申请者前期研究发现,敲低YB-1的表达可以增加NSCLC细胞对吉非替尼的敏感性, 提示YB-1与EGFR-TKIs的耐药有关。本研究拟在前期工作基础上, 通过明确YB-1在EGFR-TKIs耐药中的作用;以MAPK信号通路为切入点, 分析YB-1参与EGFR-TKIs耐药的分子机制;利用免疫共沉淀结合质谱分析筛选YB-1调控的耐药相关的靶基因；探讨YB-1在EGFR -TKIs耐药中的作用及机制。揭示YB-1与肺癌耐药的可能关系。.本项目研究结果显示，YB-1的高表达参与了非小细胞肺癌EGFR-TKIs耐药的发生，YB-1与ERK信号通路可以相互调控，且抑制ERK信号通路可以提高细胞对吉非替尼的敏感性。免疫共沉淀结合质谱分析进一步筛选出MVP、MDR1、BCRP三个蛋白可以与YB-1形成蛋白复合物，进而探讨发现MDR1干扰可以明显抑制细胞增殖并提高细胞对吉非替尼的敏感性。这是YB-1在肺癌耐药方面研究的重要成果，为指导EGFR-TKIs有效治疗提供了理论依据，拓展了对于YB-1在EGFR-TKIs耐药中重要作用的认识，为今后针对肺癌的基因治疗提供可能的新靶点。