转移性肾癌酪氨酸激酶抑制剂（TKI）靶向治疗药物耐受是临床面临的难题，研究表明其内在机制可能是一个多层面、多分子调控的过程。前期我们对术后接受舒尼替尼治疗敏感和耐药肾癌患者的标本进行高通量芯片筛选，以获得其中差异表达基因，并对芯片结果进行分析和验证，发现ANGPTL3（血管生成素类似物3）的可变剪接与肾癌舒尼替尼耐药密切相关。ANGPTL3可变剪接生成两种转录本：ANGPTL3-001（编码蛋白RNA）和ANGPTL3-003（长链非编码RNA），扩大样本在舒尼替尼、索拉非尼两个独立的组织标本队列中分别进行验证，发现两种转录本在敏感组和耐药组之间均差异表达，并且对治疗敏感性具有反向调控作用。本课题拟从分子和细胞水平研究ANGPTL3可变剪接调控肾癌TKI靶向药物耐药的机制；从荷瘤模型和临床样本中探讨ANGPTL3可变剪接体作为诊疗靶标的可行性，为预测疗效、逆转耐药提供新的理论依据。

One of the most frustrating clinical challenges to the metastatic renal cell carcinoma is the tyrosine kinase inhibitor (TKI) targeted resistance. Moreover, research shows that its internal mechanism may be a multi-level, multi-molecular regulatory process. Recently, by comparing the chip-based high throughput expression profiles of the Sunitinib-sensitive renal cell carcinoma samples with the Sunitinib-resistant ones, we have identified many differentially expressed genes. Angiopoietin Analogue 3 (ANGPTL3) is the very hit that is of our interest, due to its Sunitinib-relevant alternative splicing. Except a known polypeptide-coding transcript, ANGPTL3-001, we newly identified ANGPTL3-003 as a transcript of lncRNA. ANGPTL3-001 is highly expressed in the Sunitinib/sorafenib-sensitve samples while the ANGPTL3-003 prefers to the Sunitinib/sorafenib-resistant samples. Further, manipulating the ANGPTL3-001/ANGPTL3-003 expression level can change the renal cancer cells’ response to Sunitinib/sorafenib treatment. Thus, we propose that the ANGPTL3 alternative-splicing mode is the determining factor for the resistance to TKI targeted treatment. In this proposal, we will further investigate the mechanisms underlying the TKI targeted resistance related ANGPTL3 alternative splicing from the cellular and molecular levels. We will also explore the feasibility for the ANGPTL3 alternative splicing as a diagnostic/therapeutic target using mouse tumor-bearing models and clinical samples. The outcome of this project will provide new theoretical basis to the efficacy prediction and resistance reversal of TKI targeted treatment to the renal cell carcinoma.