新型FGFR候选新药GF008个性化特征研究——GF008获得性耐药机制探讨

With the increasing recognition of the importance of precision medicine in cancertherapy, the emergence of drug resistance has ultimately limited the benefit of targeted therapy, and presents a challenge to the treatment of cancer patients. In our laboratory, we have identified a novel, selective FGFR inhibitor candidate, designated as GF008. With the application of FGFR-addicted cancer cells, acquired-resistant cells, tumor stromal cells and xenografts, we will go insight into the mechanisms of action underlying the acquired resistance, especially the.potential role of tumor microenvironment in conferring GF008 resistance, which hopefully give rise to a rationale of drug combo-therapy for resistance. This study will provide further indication that the systematic dissection of interactions between tumor and their microenvironment can uncover important mechanisms underlying drug resistance. Expected esults will promote the drug development process of GF008 and provide preclinical evidence for GF008 clinical rational drug use to achieve precise individualized treatment. Further, this study provides example of personalized innovative drug research and development.

本课题紧紧围绕肿瘤精准治疗的国际前沿，选择肿瘤研究领域重要的前沿靶点，聚焦个性化药物研发的核心瓶颈——耐药问题为突破口，同步关注肿瘤耐药的内外因—— “肿瘤”与“肿瘤微环境”，采用FGFR依赖的肿瘤细胞、多种基质细胞、获得性耐药细胞以及动物体内模型，首次探讨具有自主知识产权的新型FGFR抑制剂GF008获得性耐药的机制，探寻新的能够预测肿瘤患者对GF008耐药的生物标志物，并关注克服耐药的联合用药方案；预期研究成果将为推动GF008研发进程、指导GF008临床科学合理用药、实现个体化精准治疗提供重要的理论基础，为个性化创新药物研发提供范例。

本课题聚焦抗肿瘤药物研发的核心瓶颈——耐药问题，以已报道的经典的FGFR小分子抑制剂和自主知识产权的新型FGFR抑制剂GF008（3D185）为探针，构建抑制剂获得性耐药体系进行耐药机制以及克服耐药策略的探索。经过课题参与人员的高效紧密分工协作，我们圆满完成了课题研究的预期目标，发现细胞因子重编程是FGFR抑制剂耐药的关键，其通过肿瘤细胞中多条生长因子受体和炎性因子受体、激活转录因子 STAT3 来驱动获得性耐药。而且肿瘤细胞与肿瘤微环境基质细胞（成纤维细胞和巨噬细胞）相互作用，导致“细胞因子分泌谱”的放大释放，加重FGFR抑制剂的耐药产生。HSP90抑制剂与HDAC抑制剂能够克服分泌组介导的耐药。研究结果为3D185等FGFR抑制剂临床病人的选择和理性联合用药提供了重要的实验依据。