mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt Journal Article
| Authors: | 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. |
| Article Title: | mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt |
| 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. ©2006 American Association for Cancer Research. |
| Keywords: | signal transduction; protein kinase b; somatomedin; clinical article; controlled study; human tissue; protein expression; protein phosphorylation; human cell; solid tumor; cell proliferation; enzyme inhibition; protein kinases; cancer cell culture; enzyme activation; cell line, tumor; protein tyrosine kinase; phosphorylation; drug synergism; protein kinase inhibitors; receptor, igf type 1; mammalian target of rapamycin; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; phosphoproteins; down regulation; negative feedback; insulin-like growth factor i; everolimus; sirolimus; somatomedin receptor; insulin receptor substrate 1 |
| Journal Title: | Cancer Research |
| Volume: | 66 |
| Issue: | 3 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-02-01 |
| Start Page: | 1500 |
| End Page: | 1508 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-05-2925 |
| PUBMED: | 16452206 |
| PROVIDER: | scopus |
| PMCID: | PMC3193604 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 731" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus" |
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