基于诱导RET表达研究凡德他尼对非小细胞肺癌治疗机理

靶向药物是当前肿瘤治疗的热门领域。凡德他尼作为多种酪氨酸激酶抑制剂，可以靶向EGFR、VEGFR以及RET，临床上被批准用于甲状腺髓样癌的治疗，并取得了良好的效果，因其可以靶向EGFR，并且具有良好的口服耐受性，在非小细胞肺癌（NSCLC）的治疗中被给予厚望。本课题组在前期工作中发现凡德他尼不仅可以抑制NSCLC细胞株Calu-6的迁移与侵袭能力，同时诱导细胞发生自噬，拮抗靶向治疗，具备双重作用。然而这一现象仅表现在RET基因高表达的细胞株中，提示RET高表达可以作为一种分子标志用以筛选对该药敏感的病人。本项目将基于先前的研究结果，探讨RET基因高表达是否可以作为一种分子标志用以指导凡德他尼治疗NSCLC以及诱导RET阴性的NSCLC细胞株表达内源性RET基因能否增加对凡德他尼的敏感性，并对其中的分子机制进行研究，从而为凡德他尼在NSCLC的临床应用提供理论依据。

Targeted drug is a hotspot of cancer therapy. The multiple tyrosine kinase inhibitor vandetanib, which can target EGFR, VEGFR and RET, is approved for clinically treatment of medullary thyroid carcinoma and achieved a good result. As vandetanib can target the EGFR and has a good oral tolerance, medical profession is setting its hopes on vandetanib in the treatment of non-small cell lung cancer (NSCLC). Our previous work found that vandetanib can not only inhibit the migration and invasion ability of NSCLC cell line Calu-6, but also induce cell autophagy to antagonize targeted therapy. However, this phenotype was unique to the NSCLC cell lines which highly expressed RET gene, prompting RET expression can be used as a molecular marker for screening the drug-sensitive patients. In this project, based on the results of previous work, we attend to explore whether the expression of RET gene can be used as a molecular marker for the guidance of vandetanib treatment of NSCLC, and whether inducing endogenous expression of RET gene in RET-negative NSCLC cell lines can increase the sensitivity of vandetanib, which will provide theoretical basis for vandetanib in the clinical application of NSCLC.