获得性耐药是肿瘤药物治疗的最大挑战之一。索拉非尼是目前FDA唯一认证的治疗晚期肝癌的靶向药物，但患者常在治疗数月后出现耐药（即获得性耐药）。研究表明获得性耐药可能是通过肿瘤细胞不断进化而产生药物抵抗，以肿瘤进化的新视角来动态、全面解析耐药机制将有望从根本上解决肿瘤获得性耐药。探寻肝癌获得性耐药进化演变规律的相关研究未见报道。在前期成功建立索拉非尼获得性耐药异种移植瘤模型(PDX)基础上，本研究拟以高度复制患者肿瘤生物学特性的PDX模型为主要载体，通过全基因组测序来绘制肝癌索拉非尼获得性耐药相关突变图谱；进一步利用靶向捕获测序在PDX连续传代肿瘤组织中筛选关键驱动基因，探讨肝癌索拉非尼获得性耐药的进化轨迹及相关机制；最后通过循环肿瘤DNA“液体活检”方式动态监测获得性耐药产生。本研究将深入揭示肝癌索拉非尼获得性耐药的进化演变规律，为肝癌耐药逆转及监测提供新思路和新方法，具有非常重要的理论和临

Acquired resistance is one of the biggest challenges to cancer drug therapy. Sorafenib is the only FDA approved targeted drug for advanced hepatocellular carcinoma (HCC), but disease-stabilizing effects are eventually followed by acquired resistance after several months of treatment. Studies indicated that treatment resistance could be acquired through continuous evolution of tumor cells. Research based on this understanding will dynamically and comprehensively unveil the mechanism of new drug resistance with the expectation to fundamentally reverse resistance. It is critical to improve the therapeutic effect of sorafenib by understanding its acquired resistance evolution, while no related research has been reported yet. Based on the successful establishment of the sorafenib acquired resistance PDX (patient derived xenograft) model, we plan to map sorafenib acquired resistance mutational profile in HCC by whole genome sequencing and further identify key driving genes in tumor tissue from continuous passages of PDX models by targeting capture sequencing. The results will help us to explore the evolutionary trajectories and related mechanisms of sorafenib acquired resistance in HCC. The last step will be dynamic monitoring acquired resistance by liquid biopsy (circulating tumor DNA). This study will reveal the mechanism of sorafenib acquired resistance evolution and offer new strategies for monitoring and reversing acquired resistance in HCC, which has a very important theoretical and clinical prospect.