胃肠道间质肿瘤（GIST）是来源于胃肠道表达KIT蛋白的间叶源性肿瘤。伊马替尼（imatinib）对初治的GIST疗效显著，然而继发性耐药已成为临床的一大难点。研究表明，自噬可以提高肿瘤细胞对化疗和靶向治疗的耐受性。近期发现，自噬是imatinib耐药的重要原因之一。我们拟采用自噬抑制剂联合imatinib处理imatinib耐药的GIST细胞，并通过RNA干扰技术阻断自噬信号通路PI3K/AKT/mTOR途径的各个蛋白，分别检测阻断后下游信号通路蛋白磷酸化水平及检测细胞自噬和凋亡水平。进一步通过体内动物实验验证。旨在阐明PTEN-PI3K/AKT/mTOR通路在imatinib诱导的细胞自噬中的作用，以及imatinib通过PTEN基因影响其下游自噬信号通路的作用，进而诱导肿瘤细胞自噬产生耐药。探讨自噬抑制剂在逆转imatinib耐药中的作用及其机制，为克服GIST耐药提供新的思路。

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract and characterized by expression of KIT protein. Most GIST have oncogenic KIT mutations that engender constitutive activation of this receptor tyrosine kinase. Treatment of advanced GIST improved dramatically following development of imatinib. Growing evidence indicates that autophagy can promote tumor cell survival in response to both cytotoxic and targeted chemotherapies. Recent studies show autophagy is one of the important reasons responsible for imatinib resistance. We plan to combine autophagy inhibitor and imatinib to treat imatinib-resistant GIST cells. After treatment, RNA interfere technology will be applied to block each protein on the autophagy signal pathway of PI3K/AKT/mTOR separately. Phosphorylated proteins of downstream signal pathway and cell autophagy and apoptosis level will be detected after RNAi. The results of vitro will be confirmed by in vivo experiments using mice model. The purpose of this study is to elucidate the role of PTEN-PI3K/AKT/mTOR signal pathway in inducing cell autophagy. We also wonder whether the downstream PI3K/AKT/mTOR pathway will be influeced by imatinib through PTEN gene, then induce tumor cells autophgy and result imatinib resistance. Thus, combining imatinib with autophagy inhibitor represents a potentially valuable strategy to overcome acquired resistance in GIST patients.

胃肠道间质肿瘤（GIST）是来源于胃肠道表达KIT蛋白的间叶源性肿瘤。伊马替尼（imatinib）对初治的GIST疗效显著，然而继发性耐药已成为临床的一大难点。研究表明，自噬可以提高肿瘤细胞对化疗和靶向治疗的耐受性。近期发现，自噬是imatinib耐药的重要原因之一。我们采用自噬抑制剂联合imatinib处理imatinib耐药的GIST细胞，并通过RNA干扰技术阻断自噬信号通路PI3K/AKT/mTOR途径的各个蛋白，分别检测阻断后下游信号通路蛋白磷酸化水平及检测细胞自噬和凋亡水平。进一步通过体内动物实验验证。我们发现，PTEN可以抑制PI3K/AKT/mTOR通路，从而逆转imatinib诱导的细胞自噬，逆转耐药；以及imatinib具有通过抑制PTEN基因表达而促进其下游自噬信号通路的作用，进而诱导肿瘤细胞自噬产生耐药。我们发现自噬抑制剂能够通过上调PTEN抑制下游PI3K/AKT/mTOR通路，抑制自噬，逆转imatinib耐药，为克服GIST耐药提供新的思路。