小细胞肺癌（SCLC）预后差与多药耐药（MDR）密切相关。我们前期研究发现EPHA3在SCLC组织中的表达与患者生存时间密切相关；EPHA3通过PI3K信号通路降低SCLC耐药性；生物信息学分析发现，RUFY1可能是EPHA3激活PI3K通路的相关功能蛋白；我们新近发现EPHA3能调控RUFY1的表达。由此，我们提出本课题假设，EPHA3通过RUFY1激活PI3K通路参与SCLC耐药。本项目拟在前期工作基础上开展以下研究：1、分析EPHA3参与SCLC耐药的功能区；2、分析EPHA3功能区改变对PI3K和RUFY1表达的影响；3、分析EPHA3和PI3K之间的相互作用；4、探讨PI3K和RUFY1基因对SCLC耐药的影响；5、在临床样本中验证细胞实验的结果。通过以上研究，明确EPHA3激活PI3K信号通路参与调控SCLC耐药性的分子机制，为进一步开展SCLC新的基因治疗靶点的研究提供依据。

Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). Our previous studies found that EPHA3 expression in SCLC tissues was correlated with longer overall survival of patients. EPHA3 decreased chemoresistance of SCLC cells via PI3K signaling pathway. Bioinformatics analysis was conducted and found that RUFY1 might be the predicted functional protein playing a role in the process of EPHA3 activating PI3K signaling pathway. Moreover, our latest study found that EPHA3 could regulate the expression of RUFY1. Therefore, we proposed a hypothesis that EPHA3 activates the PI3K signaling pathway via RUFY1 to regulate the SCLC multidrug resistance. Based on the above observations, we intend to execute the following research: 1. Perform the functional analysis of EPHA3 involved in SCLC chemoresistance; 2. Assess the effect of the functional domain change of EPHA3 on the expression of PI3K and RUFY1; 3. Investigate the interaction between EPHA3 and PI3K; 4. Explore the effect of PI3K and RUFY1 on SCLC chemoresistance; 5. Verify the results of cell experiments by detecting the clinical samples. Thus, we want to determine the molecular mechanism that EPHA3 activates the PI3K signaling pathway to regulate the SCLC multidrug resistance, and provide the basis for future studies of new molecular targeting in SCLC.