| Literature DB >> 25544636 |
Sarit Schwartz1, John Wongvipat2, Cath B Trigwell3, Urs Hancox3, Brett S Carver2, Vanessa Rodrik-Outmezguine1, Marie Will1, Paige Yellen1, Elisa de Stanchina1, José Baselga2, Howard I Scher4, Simon T Barry3, Charles L Sawyers2, Sarat Chandarlapaty5, Neal Rosen6.
Abstract
In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.Entities:
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Year: 2014 PMID： 25544636 PMCID： PMC4293347 DOI： 10.1016/j.ccell.2014.11.008
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743