Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer Journal Article
| Authors: | Carracedo, A.; Ma, L.; Teruya-Feldstein, J.; Rojo, F.; Salmena, L.; Alimonti, A.; Egia, A.; Sasaki, A. T.; Thomas, G.; Kozma, S. C.; Papa, A.; Nardella, C.; Cantley, L. C.; Baselga, J.; Pandolfi, P. P. |
| Article Title: | Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer |
| Abstract: | Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers. |
| Keywords: | signal transduction; mitogen activated protein kinase; cancer chemotherapy; controlled study; human tissue; unclassified drug; human cell; advanced cancer; dose response; drug potentiation; monotherapy; nonhuman; solid tumor; antineoplastic agents; drug megadose; neoplasm; neoplasms; animal cell; mouse; animals; mice; low drug dose; melanoma; enzyme inhibition; map kinase signaling system; mitogen activated protein kinase inhibitor; embryo; animal experiment; animal model; combination chemotherapy; cancer cell culture; enzyme activation; in vitro study; tumor xenograft; drug effect; cell line, tumor; phosphatidylinositol 3 kinase; experimental mouse; transcription factors; prostate cancer; tissue section; gene expression regulation, neoplastic; enzyme inhibitors; dosage schedule comparison; colon tumor; breast tumor; mammalian target of rapamycin; ras protein; feedback system; breast adenocarcinoma; mammalian target of rapamycin inhibitor; everolimus; rapamycin; sirolimus; immunosuppressive agents; 2 morpholino 8 phenylchromone; wortmannin; feedback, biochemical; growth inhibition; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; experimental model; 1,4 diamino 1,4 bis(2 aminophenylthio) 2,3 dicyanobutadiene; pharmacological blocking; mammalian target of rapamycin c1 |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 118 |
| Issue: | 9 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2008-09-01 |
| Start Page: | 3065 |
| End Page: | 3074 |
| Language: | English |
| DOI: | 10.1172/jci34739 |
| PUBMED: | 18725988 |
| PROVIDER: | scopus |
| PMCID: | PMC2518073 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 219" - "Export Date: 17 November 2011" - "CODEN: JCINA" - "Source: Scopus" |
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