SDH5蛋白在EGFR-TKI治疗突变型肺腺癌患者原发性耐药中的作用

EGFR-TKI is a molecular target-therapeutic agent and it improve the survival rate of the lung adenocarcinoma patients with EGFR mutations,but a problem needed to be resolved that 30% lung adenocarcinoma patients with EGFR mutation remains primary drug-resistance to the therapy of EGFR-TKI. It is generally considered that EGFR-TKI primary drug resistance have relationship with KRAS mutation,The latest studies showed that the phenomenon of EMT correlated to EGFR-TKI primary drug-resistance, our previous study revealed that SDH5 protein can regulate EMT in NSCLC,and also in our cellular experiments, knocking down the expression of SDH5 protein, we found the sensitivity of lung adenocarcinoma cells to EGFR-TKI decreased significantly. So in this project, we speculate that loss of SDH5 protein is the reason for failure of first time EGFR-TKI treatment. Western blot, Co-immunoprecipitation assay will be used. If the project be succeed, The mechanism of EGFR-TKI primary resistance will be solved, and also the study offers evidence on SDH5 as a predicting factor for EGFR-TKI treatment,it will provide a basis to accurate beneficiaries.

EGFR-TKI明显提高EGFR突变型肺腺癌患者的总生存率，但约30%的EGFR突变型肺腺癌患者对EGFR-TKI的治疗原发耐药，目前普遍认为与KRAS等基因的突变有关，然而最新研究表明：肺腺癌对EGFR-TKI的原发耐药与上皮间质化（EMT）有关，在之前的研究中我们发现琥珀酸脱氢酶5（SDH5）蛋白能调节肺腺癌的EMT，不仅如此，在EGFR-TKI原发性耐药的肺腺癌患者中，也发现SDH5蛋白的表达明显下降，在细胞实验中，沉默SDH5的表达后，肺腺癌细胞对EGFR-TKI的敏感性明显下降，因此，我们推测SDH5通过EMT导致EGFR-TKI的原发性耐药,我们将通过Western blot、免疫沉淀等验证这一假设,该课题将进一步的阐明EGFR-TKI原发性耐药的作用机制，不仅如此，SDH5还可以作为EGFR-TKI治疗肺腺癌的评价指标，为精确EGFR-TKI的受益人群打下坚实的基础。

约30%的含有EGFR活性突变的肺腺癌患者对EGFR-TKI原发性耐药，原发性耐药患者的遗传特征目前还不明确，缺乏EGFR-TKI原发性耐药相关的分子标志物，更是缺乏有效的治疗方法。我们首先进行了EMT调控蛋白SDH5在EGFR-TKI 原发耐药中的探索研究，研究结果证实SDH5与EGFR-TKI 原发耐药并没有显著的相关性。但我们发现了中国人群肺癌组织样本中Cripto-1表达与EGFR-TKI原发耐药的相关性，发现Cripto-1表达是EGFR-TKI原发耐药的分子标志物，并且是含有EGFR敏感突变肺腺癌患者生存的不良预后因素。机制研究发现分泌型Cripto-1通过激活SRC磷酸化诱导EGFR-TKI耐药。而EGFR-TKI联合 SRC inhibitor对过表达Cripto-1的肺癌细胞生长抑制具有合成效应。在Cripto-1 表达的裸鼠移植瘤模型中EGFR-TKIs 联合 SRC inhibitor显示出合成的抗肿瘤效应。我们的研究数据不仅表明Cripto-1可作为含有EGFR敏感突变肺腺癌患者对EGFR-TKI原发性耐药的分子标志物，而且EGFR-TKI联合 SRC inhibitor很可能是EGFR-TKI原发性耐药肺腺癌患者的新的治疗方案，为EGFR-TKI原发性耐药肺腺癌患者的治疗带来了新的希望，有潜在的临床应用前景。