索拉非尼是目前唯一用于进展期肝癌的一线靶向药物，但索拉非尼的原发性、获得性耐药使其疗效有限。研究索拉非尼耐药机制、探索新型肝癌靶向治疗策略是当务之急。通过基因测序显示肿瘤异质性与靶向治疗疗效及其耐药关系密切；而肿瘤微环境则是耐药的重要非基因因素。我们前期测序200余例肝癌，发现42%的病人具有靶向治疗靶点，证实ctDNA具有“液体活检”价值，建立了类器官培养及病人来源肿瘤模型（PDX）的抗肿瘤药物研究平台。本项目拟通过构建肝癌靶向深度测序方案、实时动态检测ctDNA克服肿瘤异质性，探寻索拉非尼药敏标志物及获得性耐药的基因变异，同时评估肿瘤微环境对获得性耐药的作用，并在类器官及PDX中进行验证，探索耐药干预新方法并评估超说明书使用靶向药物治疗肝癌的价值。本项目以肝癌靶向治疗为重点，发现索拉非尼的药敏标志物，提出索拉非尼获得性耐药干预和靶向治疗新策略，为改善肝癌病人精准用药提供理论和实验依据。

Sorafenib is the only first-line target drug used in advanced hepatocellular carcinoma (HCC), but its effect has been limited by its primary and acquired drug resistance. It is urgent to explore the mechanism of drug resistance to sorafenib and to develop novel target therapeutic strategies for HCC patients. Through gene sequencing, it’s revealed that tumor heterogeneity is closely correlated with the therapeutic effect and drug resistance of targeted therapy; meanwhile, tumor microenvironment acts as an important non-genetic factor in drug resistance. Our previous work of sequencing on more than 200 HCCs found that 42% patients harbored targeted therapeutic sites and we also validated the liquid biopsy value of circulating tumor DNA (ctDNA). Meanwhile, we established an anti-tumor drug research and development platform using organoid culture and patient derived xenograft (PDX). This study will establish HCC-specific targeted deep sequencing and detect ctDNA in real-time and dynamic manner to overcome tumor heterogeneity, aiming to screen for drug-sensitivity markers of sorafenib and gene variations that caused acquired drug resistance. The role of microenvironment on acquired drug resistance would be assessed and further verified in organoid culture and PDX models. The intervention strategies of drug resistance as well as the value of off-label use of target drug in HCC treatment will also be explored. In summary, our study focuses on the target therapy of HCC, trying to find biomarkers for predicting sensitivity to sorafenib, identify the mechanism of its acquired drug-resistance, and propose novel strategies for target therapy in HCC, which would provide theoretical and experimental evidence for the precision medication of HCC patients.