如何提升食管癌对化疗药物的敏感性，甄选化疗增敏剂获益人群，探索相关机制成为中晚期食管癌药物治疗的重要议题。我们前期的体内外实验发现LB100增加食管癌对化疗的敏感性，但PIK3CA突变下调PPP2R2D表达却干预LB100化疗增敏作用。为进一步验证并揭示其分子机制，本项目拟利用课题组已拥有的PIK3CA突变/野生PDECXM模型、衍生的PDECC、商品化食管癌细胞系，以及PPP2R2D敲低和过表达的细胞株，采用形态、分子、细胞生物学技术，证实PIK3CA突变导致LB100化疗增敏失效依赖于PPP2R2D，同时明确PIK3CA突变介导PPP2R2D低表达的作用靶点及其调控网络，由此揭示其分子效应途径。在此基础上，检测食管癌患者样本中PIK3CA突变、PPP2R2D及其上游调控节点分子的表达情况，结合临床资料进行相关性和预后分析，为LB100在食管癌开展临床应用的个体化人群筛选奠定理论基础。

How to improve the chemosensitization, select the patients who could benefit from chemosensitization, and explore the related mechanisms, has become the important issue in the treatment of advanced esophageal cancer (EC). In vitro and in vivo experiments, we found LB100 enhance the chemosensitivity of EC, however, the down-regulation of PPP2R2D expression caused by PIK3CA mutation interfere the effect of LB100 chemosensitization. In order to further verify and reveal the mechanism, we would utilize patient-derived esophageal cancer xenograft mouse models (PDECXM), PDECXM derived cell lines (PDECC), commercialized EC cell lines with or without PIK3CA mutation, as well as EC cell lines with up and down regulated PPP2R2D expression, by using morphological, molecular and cellular biology techniques, to certify the ineffectiveness of LB100 chemosensitization in PDECXM and cell lines with PIK3CA mutation depends on the low PPP2R2D expression. At the same time, we would explicit the key molecular and the regulatory network through which PIK3CA mutation down regulated PPP2R2D expression, and reveal the molecular pathway. Based on these results, the state of PIK3CA mutation and the expression of PPP2R2D and its upstream key molecular would be detected in EC patients. The correlation and prognostic analysis would also be conducted, to lay the foundation for the screening of personalized patients in the future clinical application of LB100 in EC.