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multi-level targeting of the phosphatidylinositol-3-kinase pathway in non-small cell lung cancer cells多层次目标phosphatidylinositol-3-kinase途径的非小细胞肺癌细胞.pdf

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multi-level targeting of the phosphatidylinositol-3-kinase pathway in non-small cell lung cancer cells多层次目标phosphatidylinositol-3-kinase途径的非小细胞肺癌细胞

Multi-Level Targeting of the Phosphatidylinositol-3- Kinase Pathway in Non-Small Cell Lung Cancer Cells 1 1 1 1 3 Christopher R. Zito , Lucia B. Jilaveanu , Valsamo Anagnostou , David Rimm , Gerold Bepler , 4 4 1 1 1,2 Sauveur-Michel Maira , Wolfgang Hackl , Robert Camp , Harriet M. Kluger , Herta H. Chao * 1 Yale University School of Medicine Yale Comprehensive Cancer, New Haven, Connecticut, United States of America, 2 Medical Service, VA Connecticut Healthcare System, West Haven, Connecticut, United States of America, 3 Karmanos Cancer Institute, Detroit, Michigan, United States of America, 4 Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America Abstract Introduction: We assessed expression of p85 and p110a PI3K subunits in non-small cell lung cancer (NSCLC) specimens and the association with mTOR expression, and studied effects of targeting the PI3K/AKT/mTOR pathway in NSCLC cell lines. Methods: Using Automated Quantitative Analysis we quantified expression of PI3K subunits in two cohorts of 190 and 168 NSCLC specimens and correlated it with mTOR expression. We studied effects of two PI3K inhibitors, LY294002 and NVP- BKM120, alone and in combination with rapamycin in 6 NSCLC cell lines. We assessed activity of a dual PI3K/mTOR inhibitor, NVP-BEZ235 alone and with an EGFR inhibitor. Results: p85 and p110a tend to be co-expressed (p,0.001); p85 expression was higher in adenocarcinomas than squamous cell carcinomas. High p85 expression was associated with advanced stage and poor survival. p110a expression correlated with