PI3K/AKT/mTOR通路中的AKT及MTOR等的磷酸化水平高低与非小细胞肺癌的生物学特征关系密切。有研究5371 纳入了79例晚期肺鳞癌患者，通过二代测序技术进行分析发现，含PI3K突变的患者与不含PI3K突变的患者相比，中位生存期更差(8.6mvs 19.1m, P<0.001)， 更易发生远处转移(18% vs 3%，P<0.05)，更易发生脑转移(27% vs 0%，P<0.01)。 通过进-一步的全外显子测序发现，有脑转移的患者有着更高的PTEN缺失率。除此之外，PIK3CA 的突变和扩增作为不同的基因遗传学变异，对于肺鱗癌的生物学特性及靶向治疗反应，有着不同的临床意义。有学者发现PEBP4 ( Phosphatidylethanolamnine binding protein 4)作为PI3K的下游信号分子，其过表达可以激活AKT和MTOR的磷酸化，促进非小细胞肺癌的生长和侵袭。另外，目前发现的与肿瘤生长和侵袭关系密切的ILT4 (Immunoglobulin like transcription factor 4)， WSTF (Willianssyndrome transcription factor) 以及miRNA ( 如miRNA-107 等)，可以通过PI3K/AKT/mTOR信号通路发挥其生物学功能。

图3-3 PI3K/AKT/mTOR通路。受体与配体结合后，激活的IA型PI3K在细胞膜上将PIP2转化为PIP3。与此同时，通过PI3K的交互作用，RAS/RAF/MAPK通路也被激活。PIP3 作为第2信使结合AKT的PH结构域，促使PDK1磷酸化AKT蛋白，导致AKT活化。活化的AKT导致TSC2/TSC1 复合物磷酸化和失活，进一步引起RHEB的聚集并抑制，最终导致mTORC1的活化。mTORC1活化后可以增强蛋白翻译，抑制细胞自噬。磷酸化的AKT除了活化mTOR信号外，也可以活化MDM2和FOXO。FOXO的活化导致细胞周期抑制。PI3K= 胞内磷脂腺肌醇激酶; PIP2= 4,5-二磷酸脂酰肌醇; 磷脂酰肌醇-3, 4, 5-三磷酸; PTEN=人第10号染色体缺失的磷酸酶; PDK1= phosphoinositide dependent kinase-1; TSC=结节性硬化症相关蛋白; RHEB=Ras homologenriched in brain; mTORC1= 雷帕霉素机能靶标蛋白复合物1; MDM2=murine double minute 2; BAD=Bcl2 相关细胞死亡激动剂; FOXO=forkhead box O; PHLPP=PH domain leucine-rich repeat protein phosphatase。

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