AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity (Cancer Cell, 2010, 19:58-71)

報告日期: 2011/03/25
報告時間: 15:10/16:00
報告學生: 許太乙 (英文報告)
講評老師: 呂增宏

Full Text: http://basicmed.med.ncku.edu.tw/admin/up_img/0325-3.pdf

AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Sarat Chandarlapaty,Ayana Sawai, et al.
Cancer Cell 16, 425–438, November 3, 2009
Speaker: 許太乙
Committer: 呂增宏 Ph.D
In present studies indicated cancer cells has highly AKT phosohorylation and RTKs expressioin. The cause of this AKT pathway hyperactivity is 1) activation of RTKs by mutation (epidermal growth factor receptor) or gene amplification (HER2) (2) activating mutations of components of the pathway such as PI3K or AKT (3) deletion or decreased function of tumor suppressors such as the PIP3 phosphates, and tensin homolog (PTEN).
in past study indicated Tumors with PTEN or PIK3CA mutations or HER2 amplification have been shown to be dependent on PI3K-AKT-mTOR signaling for maintenance of the transformed phenotype and hypersensitive to inhibition of its components.
HER2 amplification cancer cell were treated with AKTi-1/2 which promoted the HER3 phosphorylation and expression. RTKs expression and phosphorylation are induced by AKT inhibition in multiple tumor types. The induction of IR, HER3 and IGF1R protein occurred in all of test tumor cell lines. Cancer cell lines treated with HER kinase inhibitor dose not block AKT inhibitor stimulated RTK expression, but HER kinase inhibitor can alleviate AKTi induction of P-RTKs. Inhibition of AKT but not mTORC induces HER3, IGF-1R and IR expression. RTK transcription increased by AKT inhibition. Combined AKTi and HER1/2 kinase inhibitor can improve anticancer efficacy in vivo.
This paper indicates AKT inhibitor and mTORC inhibitor are through FOXO signaling pathway to negative feedback enhance cell proliferation. This result demonstrate in cancer therapy whether effective inhibition of both PI3K-AKT signaling and feedback reactivated pathways will have an enhanced therapeutic index will have to be evaluated in clinical trials.
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