AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity Journal Article

   


Authors: Chandarlapaty, S.; Sawai, A.; Scaltriti, M.; Rodrik-Outmezguine, V. ; Grbovic-Huezo, O.; Serra, V.; Majumder, P. K.; Baselga, J.; Rosen, N.
Article Title: AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Abstract: Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone. © 2011 Elsevier Inc.
Keywords: protein kinase b; controlled study; protein expression; unclassified drug; human cell; nonhuman; mouse; enzyme inhibition; animal experiment; animal model; protein; antineoplastic activity; enzyme activity; protein tyrosine kinase; phosphatidylinositol 3 kinase; somatomedin c receptor; enzyme phosphorylation; gefitinib; single drug dose; negative feedback; lapatinib; protein mtorc1; phosphatidylinositol 3 kinase inhibitor; insulin receptor; protein her3; protein kinase b inhibitor; transcription factor foxo
Journal Title: Cancer Cell
Volume: 19
Issue: 1
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2011-01-18
Start Page: 58
End Page: 71
Language: English
DOI: 10.1016/j.ccr.2010.10.031
PROVIDER: scopus
PMCID: PMC3025058
PUBMED: 21215704
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-78651458656&partnerID=40&md5=388d87cb0f35716259d7b0aa6f42b185
Notes: --- - "Export Date: 4 March 2011" - "CODEN: CCAEC" - "Source: Scopus"
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MSK Authors
  1. Neal Rosen
    425 Rosen
  2. Sarat Chandarlapaty
    284 Chandarlapaty
  3. Olivera Grbovic-Huezo
    26 Grbovic-Huezo
  4. Vanessa Sofi Rodrik - Outmezguine
    24 Rodrik - Outmezguine
  5. Ayana Sawai
    17 Sawai
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