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

我们通过对子宫内膜癌全基因组的全面调查，阐明了参与Ras-PI 3 K通路激活的各种因素。此外，我们评估了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，显示致癌突变AKT 1（E17 K）突变在子宫内膜癌样本。我们在89例子宫内膜癌中的2例（2.2%）中检测到AKT 1（E17 K）突变。这两种AKT 1突变肿瘤在Ras-PI 3 K通路中的PIK 3CA、PTEN和K-Ras中不具有任何其他突变。我们对31例子宫内膜癌进行了全面的基因组调查，以了解Ras-PI 3 K通路基因的染色体不平衡、微卫星不稳定性（MSI）状态和突变状态。我们在29%的患者中检测到5个或更多拷贝数变化（归类为CIN广泛），55%检测到1 - 4个变化（CIN中间），16%检测到无变化（CIN阴性）。与CIN-中等/阴性肿瘤相比，阳性MSI在CIN-广泛肿瘤中较少见。多因素分析显示，CIN-广泛是一个独立的预后不良因素。我们证明了Ras-PI 3 K通路的基因组改变在子宫内膜癌中非常普遍，无论基因组不稳定的类型如何.我们将RAD 001（依维莫司，一种mTOR抑制剂）加入到13种子宫内膜癌细胞系中。我们通过MTT测定证实，RAD 001抑制这些细胞中的细胞增殖，特别是在Ras-PI 3 K途径中具有PIK 3CA、PTEN和/或K-Ras突变的11个细胞系中的10个中。

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.