尽管EGFR-TKI（TKI）对具有EGFR突变的肺腺癌患者疗效显著，但是仍然还有约30%的EGFR敏感突变的肺腺癌患者对TKI的首次治疗无效，并且缺乏预测分子标志物。最近研究报道，Cripto1(CR1)通过激活Src诱导EGFR突变的肺癌细胞对TKI原发耐药。CR1既能锚定到细胞膜上也能分泌到细胞外，但分泌型CR1在TKI原发耐药中的作用并不清楚。我们前期研究证实分泌型CR1也能诱导TKI原发耐药。本课题中，拟进一步研究分泌型CR1蛋白导致EGFR突变肺癌细胞对TKI原发耐药的机制，探讨外周血中CR1蛋白水平是否可作为预测EGFR突变患者对TKI敏感性的预测因子，我们的研究不仅会进一步阐明TKI首次治疗EGFR突变肺腺癌患者无效的分子机制，也可能为TKI耐药提供无创检测分子标志物指导EGFR突变肺腺癌患者的治疗，具有重要的临床应用价值。

Despite impressive clinical response to EGFR-TKI (TKI), approximately 30% of lung adenocarcinoma patients harboring EGFR-sensitizing mutations exhibit primary resistance. Until now there is no effective predictor marker for TKI primary resistance. Recently, one study reported that Cripto1 (CR1) expression in EGFR-mutant NSCLC elicits TKI primary resistance through Src activation. CR1 can be present in membrane-bound and secreted form, however, the role of secreted CR1 in TKI primary resistance was still unknown. Our preliminary work showed that secreted CR1 could also induce TKI primary resistance. The aim of this study was to further investigate the mechanism of TKI primary resistance induced by secreted CR1 and explore whether the level of secreted CR1 in peripheral blood could be a predictive marker for TKI primary resistance. Moreover, we will further uncover the mechanism of TKI primary resistance, and it was also possible to provide noninvasive detection for TKI primary resistance to guide the treatment for EGFR-mutant lung adenocarcinoma patients, which may have important clinical value.