Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ Journal Article

Authors: Schwartz, S.; Wongvipat, J.; Trigwell, C. B.; Hancox, U.; Carver, B. S.; Rodrik-Outmezguine, V. ; Will, M.; Yellen, P.; de Stanchina, E.; Baselga, J.; Scher, H. I.; Barry, S. T.; Sawyers, C. L.; Chandarlapaty, S.; Rosen, N.
Article Title: Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ
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. © 2015 Elsevier Inc.
Keywords: signal transduction; protein phosphorylation; unclassified drug; gene mutation; human cell; nonhuman; mouse; enzyme inhibition; animal experiment; in vivo study; tumor regression; prostate cancer; cancer inhibition; human cell culture; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; androgen receptor; negative feedback; phosphotransferase; phosphatidylinositol 3 kinase inhibitor; phosphatidylinositol 3 phosphate; human; priority journal; article; prostate cancer cell line; lncap cell line; alpelisib; azd 8186; phosphatidylinositol 3 kinase alpha; phosphatidylinositol 3 kinase beta; bt 549 cell line
Journal Title: Cancer Cell
Volume: 27
Issue: 1
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2015-01-12
Start Page: 109
End Page: 122
Language: English
DOI: 10.1016/j.ccell.2014.11.008
PROVIDER: scopus
PMCID: PMC4293347
PUBMED: 25544636
Notes: Export Date: 3 June 2015 -- Source: Scopus
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