基于ex vivo模型联合多组学手段绘制胃癌曲妥珠单抗继发耐药机制并探索克服耐药策略

曲妥珠单抗是胃癌获批的唯一一线靶向药，可延长HER2阳性患者生存，但严重阻碍患者获益的继发耐药是全球关注热点和难点，临床亟需解决。曲妥珠单抗继发耐药机制至今无定论的主要原因，是缺乏能高度模拟患者特征的耐药研究模型，且前期研究多局限于某一层面、缺乏深入验证。运用胃癌曲妥珠单抗敏感与继发耐药配对PDX(patient-derived xenograft)模型，我们发现多分子或通路如HER2家族分子、MAPK及WNT通路等参与继发耐药。基于此，本研究拟利用间接体内(ex vivo)模型及患者标本，从组织、细胞及外泌体等多水平出发，联合包括DNA、RNA及蛋白在内的多组学手段筛选并验证参与曲妥珠单抗继发耐药的关键分子或通路，以此绘制分子网络调控图，并选择关键节点抑制剂或采用RNA干扰手段探索克服继发耐药策略及机制。该“发现-验证-克服耐药”的链条式研究旨在将研究结果转化至临床，推动开展临床试验。

Trastuzumab is the only first-line molecular target drug approved for gastric cancer and it can prolong the survival of HER2-positive patients. However, secondary resistance which seriously affects the benefit of patients is a global concern and difficulty, and needs to be solved urgently in clinical practice. The main reason why the mechanism of secondary resistance to trastuzumab has not yet been concluded is that there is a lack of drug resistance research models that can highly simulate the characteristics of patients. Moreover, the previous studies are mostly limited to a certain level, and have not been further verified. Using trastuzumab-sensitive and trastuzumab-resistant PDX (patient-derived xenograft) models, we have found many molecules and pathways involved in secondary resistance including HER2 families, MAPK and WNT pathways. Based on this, this study aims to screen out and validate the critical molecules or pathways involved in trastuzumab secondary resistance by using ex vivo models and multi-omics methods including DNA, RNA and protein from the tissue, cell and exosome levels in vitro and in vivo.The regulatory network of trastuzumab resistance will be drawn followed by exploring the strategy and mechanism of overcoming trastuzumab resistance via selecting key inhibitors or RNA interference. This study of “discovery-validation-overcoming drug resistance” aims to translate preclinical results into clinical practice to propel the clinical trials.