mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt

Kathryn E. O'Reilly, Fredi Rojo, Qing Bai She, David Solit, Gordon B. Mills, Debra Smith, Heidi Lane, Francesco Hofmann, Daniel J. Hicklin, Dale L. Ludwig, Jose Baselga, Neal Rosen

    Research output: Contribution to journalArticle

    1938 Scopus citations

    Abstract

    Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.

    Original languageEnglish (US)
    Pages (from-to)1500-1508
    Number of pages9
    JournalCancer Research
    Volume66
    Issue number3
    DOIs
    StatePublished - Feb 1 2006

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    O'Reilly, K. E., Rojo, F., She, Q. B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., Baselga, J., & Rosen, N. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Research, 66(3), 1500-1508. https://doi.org/10.1158/0008-5472.CAN-05-2925