CBP基因低表达促进EMT发生介导肺腺癌对厄洛替尼耐药的机制研究

Lung cancer is the most common malignant tumor, tyrosine kinase inhibitor (TKIs) is the standard therapeutic drug for the treatment of EGFR mutation positive in lung adenocarcinoma. However, drug resistance restricts the further application of TKIs. Researches have shown that the main mechanisms of EGFR-TKIs resistance are EGFR secondary mutations mutation (T790M), other signal pathways activation and cell pattern changes (EMT)，and the mechanism of EMT is not yet clear. Our previous study found that knockdown of the histone acetylation family gene CBP can lead to occurrence of EMT in PC-9 cell, and resistance to erlotinib, the immunohistochemistry results of lung adenocarcinoma tissue samples showed the CBP expression was lower in the erlotinib resistance group than the sensitive group. We propose the hypothesis that CBP gene can regulate EMT and result erlotinib resistance in lung adenocarcinoma. Based on the model of lung adenocarcinoma, by using genomics, cell biology method and experimental zoology, the project is mainly to study the relationship between CBP knockdown and the EMT occurrence, and the effect of erlotinib resistance from cell level, animal model and tissue samples level, further detect the mechanism of CBP regulating the occurrence of EMT. It will be helpful to further elucidate the mechanism of EGFR-TKIs resistance in lung adenocarcinoma, and provide a new way of treating lung adenocarcinoma with TKIs resistance.

肺癌是最常见的恶性肿瘤，酪氨酸激酶抑制剂（TKIs）是目前EGFR突变阳性肺腺癌的标准治疗药物，但耐药已成为影响TKIs疗效的主要原因，已知的TKIs耐药机制包括EGFR继发突变如T790M突变、旁路信号通路激活、上皮间质转化（EMT）等，其中，EMT具体的发生过程及机制尚不清楚。本课题组前期研究发现，组蛋白乙酰化家族基因CBP敲低可以导致肺腺癌细胞PC-9发生EMT，并对EGFR-TKIs厄洛替尼耐药；肿瘤组织样本中，厄洛替尼耐药组CBP表达低于敏感组。提出了CBP基因可通过调节EMT发生介导肺腺癌对厄洛替尼耐药这一假说，拟以肺腺癌为模型，运用基因组学、细胞生物学和实验动物学方法，从细胞水平、动物模型和临床样本层面研究CBP基因低表达对EMT发生以及厄洛替尼耐药的影响，探讨CBP如何调节EMT发生，有助于进一步阐明肺腺癌EGFR-TKIs耐药机制，为解决TKIs耐药问题提供新的思路。

肺癌是最常见的恶性肿瘤，严重威胁人类的健康，酪氨酸激酶抑制剂(TKIs)是目前EGFR突变阳性肺腺癌的标准治疗药物，但耐药已成为影响TKIs疗效的主要原因，已知的TKIs耐药机制包括EGFR继发突变如 T790M突变、旁路信号通路激活、上皮间质转化(EMT)等，其中，EMT具体的发生过程及机制尚不清楚。本课题组前期研究发现，组蛋白乙酰化家族基因CBP敲低可以导致肺腺癌细胞PC-9 发生EMT，并对EGFR-TKIs厄洛替尼耐药;肿瘤组织样本中，厄洛替尼耐药组CBP表达低于敏感组。提出了CBP基因可通过调节EMT发生介导肺腺癌对厄洛替尼耐药这一假说，本课题以肺腺癌为模版，针对除了EGFR 继发突变和旁路激活两个已经研究比较透彻的机制以外的第三类耐药机制，即细胞模式转化 EMT 进行进一步深入研究，从细胞水平、动物模型等层面研究CBP基因低表达对EMT发生以及厄洛替尼耐药的影响，本课题通过研究发现:(1)组蛋白乙酰化家族基因CBP 低表达导致AKT磷酸化，促进 EMT 发生，介导肺腺癌对 EGFR-TKIs 厄洛替尼耐药;(2) 在CBP敲低的PC-9细胞中，使用 HDAC 抑制剂 SAHA 处理后，能明显杀伤肿瘤细胞，明确了CBP导致 EMT 发生的相关机制，探索了组蛋白乙酰化基因参与 EGFR-TKIs 耐药的 机制; (3) 鉴于CBP 基因在调节 EGFR-TKIs 耐药方面具有重要作用，拓宽了我 们对EGFR-TKIs耐药机制认识，可作为临床上解决 EGFR-TKIs 耐药一个新的潜在靶点，具有一定的临床意义。