Anti-tumor activity of p110 isoform selective inhibitors targeting Ras-PI3K pathway.

我们通过对子宫内膜癌的全基因组综合调查，阐明了参与Ras-PI3K通路激活的各种因素。此外，我们还评估了一种mTOR抑制剂在子宫内膜癌细胞系中的抗肿瘤活性。我们发表了第一份报告，显示子宫内膜癌样本中AKT1 （E17K）突变的致癌突变。我们在89例子宫内膜癌中的2例（2.2%）中检测到AKT1 （E17K）突变。这两种AKT1突变肿瘤不具有Ras-PI3K通路中PIK3CA、PTEN和K-Ras的任何其他突变2。我们对31例子宫内膜癌的染色体失衡、微卫星不稳定性（MSI）状态和Ras-PI3K通路基因的突变状态进行了全面的基因组调查。29%的人检测到5个或更多的拷贝数变化（被归类为cin广泛），55%的人检测到1到4个变化（cin中间），16%的人检测到没有变化（cin阴性）。与cin中度/阴性肿瘤相比，cin广泛肿瘤中MSI阳性较少。多因素分析显示cin广泛是一个独立的不良预后因素。我们证明了Ras-PI3K通路的基因组改变在子宫内膜癌中非常普遍，与基因组不稳定的类型无关。我们将RAD001（依维莫司，一种mTOR抑制剂）加入13个子宫内膜癌细胞系。我们通过MTT实验证实，RAD001抑制了这些细胞的细胞增殖，特别是在Ras-PI3K通路中PIK3CA、PTEN和/或K-Ras突变的11个细胞系中的10个细胞系中。

We elucidated various factors involved in the Ras-PI3K pathway activation through genome-wide comprehensive survey in endometrial carcinomas. In addition, we evaluated anti-tumor activity of an mTOR inhibitor in endometrial cancer cell lines.1. We published the first report showing oncogenic mutation of AKT1 (E17K) mutation in endometrial cancer samples. We detected AKT1 (E17K) mutations in two out of the 89 endometrial carcinomas (2.2%). These two AKT1 mutant tumors do not possess any other mutations in PIK3CA, PTEN and K-Ras in the Ras-PI3K pathway.2. We performed a comprehensive genomic survey in 31 endometrial carcinomas for chromosomal imbalances, microsatellite instability (MSI) status and mutational status in the Ras-PI3K pathway genes. We detected five or more copy number changes (classified as CIN-extensive) in 29%, one to four changes (CIN-intermediate) in 55%, and no changes (CIN-negative) in 16%. Positive MSI was less common in CIN-extensive tumors, compared with CIN-intermediate/negative tumors. Multivariate analysis showed that CIN-extensive is an independent poor prognostic factor. We demonstrated that genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability.3. We added RAD001 (everolimus, an mTOR inhibitor) to 13 endometrial cancer cell lines. We confirmed by MTT assay that RAD001 suppressed cell proliferation in these cells, especially in ten out of the eleven cell lines with mutations of PIK3CA, PTEN and/or K-Ras in the Ras-PI3K pathway.