Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal
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RESEARCH
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Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer Aymen A Elfiky1, Saadia A Aziz2, Patricia J Conrad2, Summar Siddiqui3, Wolfgang Hackl4, Michel Maira4, Camp L Robert3 and Harriet M Kluger2*
Abstract Background: PI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials, while mTOR is the target of approved drugs for metastatic renal cell carcinoma (RCC). We characterized expression of p85 and p110a PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro. Methods: We employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescencebased method of Automated Quantitative Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which co-targets PI3K and mTOR. Results: p85 expression was associated with high stage and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly associated with decreased survival, and high p85 was independently prognostic on multivariable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC50s in the low hM range and resultant PARP cleavage. Conclusions: High PI3K and mTOR expression in RCC defines populations with decreased survival, suggesting that they are good drug targets in RCC. These targets tend to be co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting in RCC warrants further investigation.
Background Renal cell carcinoma (RCC) is among the ten leading causes of cancer-related deaths, and the incidence has been increasing by approximately 2% per year [1-4]. RCC is typically resistant to chemotherapy and radiation therapy. The five-year survival rate is 90.8% for localized RCC (confined to primary site), 63.3% for cases with regional disease, and 11.1% in patients with distant * Correspondence: [email protected] 2 Section of Medical Oncology, Yale Cancer Center, Yale University, 333 Cedar St, New Haven, CT 06520, United States of America Full list of author information is available at the end of the article
metastases [5]. The immunogenicity of RCC has been the basis for use of cytokines such as interleukin-2 and interferon for metastatic RCC, which benefit about 15% of patients [6,7]. Alternative drugs are needed for patients who are not responsive and/or are intolerant to these therapies. A growing understanding of the pathogenesis of RCC has enabled us to identify factors pertinent to development of RCC-targeting therapies. The di
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