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[Cancer Research 66, 1500-1508, February 1, 2006]
© 2006 American Association for Cancer Research

Cell, Tumor, and Stem Cell Biology

mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt

Kathryn E. O'Reilly1, Fredi Rojo2, Qing-Bai She1, David Solit1, Gordon B. Mills3, Debra Smith3, Heidi Lane4, Francesco Hofmann4, Daniel J. Hicklin5, Dale L. Ludwig5, Jose Baselga2 and Neal Rosen1

1 Memorial Sloan-Kettering Cancer Center New York, New York; 2 Vall d'Hebron University Hospital, Barcelona, Spain; 3 The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 4 Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and 5 ImClone Systems Incorporated, New York, New York

Requests for reprints: Neal Rosen, Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, Box 271, 1275 York Avenue, New York, NY 10021. Phone: 212-639-2369; Fax: 212-717-3627; E-mail: rosenn{at}mskcc.org.

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. (Cancer Res 2006; 66(3): 1500-8)




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