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

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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.