The PI3K/AKT/mTOR signaling pathway is constitutively active in PTEN-deficient cancer cells, and its targeted inhibition has significant anti-tumor effects. However, the efficacy of targeted therapies is often limited due to drug resistance. The relevant signaling pathways in PTEN-deficient cancer cells treated with the PI3K/mTOR inhibitor BEZ235 were screened using a phosphokinase array, and further validated following treatment with multiple PI3K/AKT/mTOR inhibitors or AKT knockdown. The correlation between PTEN expression levels and STAT3 kinase phosphorylation in the tissue microarrays of gastric cancer patients was analyzed by immunohistochemistry. Cell proliferation and clonogenic assays were performed on the suitably treated PTEN-deficient cancer cells. Cytokine arrays, small molecule inhibition and knockdown assays were performed to identify related factors. PTEN-deficient tumor xenografts were established in nude mice that were treated with PI3K/AKT/mTOR and/or STAT3 inhibitors. PTEN deficiency was positively correlated with low STAT3 activity. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. Our findings provide a scientific basis for a novel treatment strategy in cancer patients with PTEN deficiency.

PI3K / AKT / mTOR信号通路在PTEN缺陷型癌细胞中具有组成性活性，其靶向抑制作用具有显着的抗肿瘤作用。然而，由于耐药性，靶向疗法的功效常常受到限制。使用磷酸激酶阵列筛选用PI3K / mTOR抑制剂BEZ235处理的PTEN缺陷型癌细胞中的相关信号通路，并在用多种PI3K / AKT / mTOR抑制剂或AKT敲除后进一步验证。通过免疫组织化学分析了胃癌患者组织芯片中PTEN表达水平与STAT3激酶磷酸化的相关性。在适当治疗的PTEN缺陷型癌细胞上进行细胞增殖和克隆形成测定。细胞因子阵列 进行小分子抑制和敲低分析以鉴定相关因素。在用PI3K / AKT / mTOR和/或STAT3抑制剂治疗的裸鼠中建立了PTEN缺陷的肿瘤异种移植物。PTEN缺乏与STAT3活性低呈正相关。PI3K / mTOR抑制剂可增加巨噬细胞迁移抑制因子（MIF）的表达和分泌，并激活JAK1 / STAT3信号通路。癌细胞和体内肿瘤异种移植物均显示，PI3K / AKT / mTOR和STAT3活性的联合抑制作用增强了BEZ235对PTEN缺陷型癌细胞增殖的抑制作用。我们的发现为患有PTEN缺乏症的癌症患者的新型治疗策略提供了科学依据。在用PI3K / AKT / mTOR和/或STAT3抑制剂治疗的裸鼠中建立了PTEN缺陷的肿瘤异种移植物。PTEN缺乏与STAT3活性低呈正相关。PI3K / mTOR抑制剂可增加巨噬细胞迁移抑制因子（MIF）的表达和分泌，并激活JAK1 / STAT3信号通路。癌细胞和体内肿瘤异种移植物均显示，PI3K / AKT / mTOR和STAT3活性的联合抑制作用增强了BEZ235对PTEN缺陷型癌细胞增殖的抑制作用。我们的发现为患有PTEN缺乏症的癌症患者的新型治疗策略提供了科学依据。在用PI3K / AKT / mTOR和/或STAT3抑制剂治疗的裸鼠中建立了PTEN缺陷的肿瘤异种移植物。PTEN缺乏与STAT3活性低呈正相关。PI3K / mTOR抑制剂可增加巨噬细胞迁移抑制因子（MIF）的表达和分泌，并激活JAK1 / STAT3信号通路。癌细胞和体内肿瘤异种移植物均显示，PI3K / AKT / mTOR和STAT3活性的联合抑制作用增强了BEZ235对PTEN缺陷型癌细胞增殖的抑制作用。我们的发现为患有PTEN缺乏症的癌症患者的新型治疗策略提供了科学依据。PI3K / mTOR抑制剂可增加巨噬细胞迁移抑制因子（MIF）的表达和分泌，并激活JAK1 / STAT3信号通路。癌细胞和体内肿瘤异种移植物均显示，PI3K / AKT / mTOR和STAT3活性的联合抑制作用增强了BEZ235对PTEN缺陷型癌细胞增殖的抑制作用。我们的发现为患有PTEN缺乏症的癌症患者的新型治疗策略提供了科学依据。PI3K / mTOR抑制剂可增加巨噬细胞迁移抑制因子（MIF）的表达和分泌，并激活JAK1 / STAT3信号通路。癌细胞和体内肿瘤异种移植物均显示，PI3K / AKT / mTOR和STAT3活性的联合抑制作用增强了BEZ235对PTEN缺陷型癌细胞增殖的抑制作用。我们的发现为患有PTEN缺乏症的癌症患者的新型治疗策略提供了科学依据。