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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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S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chene, A. De Pover, K. Schoemaker, et al.
Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Mol. Cancer Ther., July 1, 2008; 7(7): 1851 - 1863.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
C. Tarn, L. Rink, E. Merkel, D. Flieder, H. Pathak, D. Koumbi, J. R. Testa, B. Eisenberg, M. von Mehren, and A. K. Godwin
Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors
PNAS, June 17, 2008; 105(24): 8387 - 8392.
[Abstract] [Full Text] [PDF]

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 Genes Dev.Home page
H. C. Dan, M. J. Cooper, P. C. Cogswell, J. A. Duncan, J. P.-Y. Ting, and A. S. Baldwin
Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK
Genes & Dev., June 1, 2008; 22(11): 1490 - 1500.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
J. A. Garcia and D. Danielpour
Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies
Mol. Cancer Ther., June 1, 2008; 7(6): 1347 - 1354.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
K. K. Mann, M. Colombo, and W. H. Miller Jr.
Arsenic trioxide decreases AKT protein in a caspase-dependent manner
Mol. Cancer Ther., June 1, 2008; 7(6): 1680 - 1687.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
H. M.W. Verheul, B. Salumbides, K. Van Erp, H. Hammers, D. Z. Qian, T. Sanni, P. Atadja, and R. Pili
Combination Strategy Targeting the Hypoxia Inducible Factor-1{alpha} with Mammalian Target of Rapamycin and Histone Deacetylase Inhibitors
Clin. Cancer Res., June 1, 2008; 14(11): 3589 - 3597.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
L. Meikle, K. Pollizzi, A. Egnor, I. Kramvis, H. Lane, M. Sahin, and D. J. Kwiatkowski
Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function
J. Neurosci., May 21, 2008; 28(21): 5422 - 5432.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
G. Johansson, Y. Y. Mahller, M. H. Collins, M.-O. Kim, T. Nobukuni, J. Perentesis, T. P. Cripe, H. A. Lane, S. C. Kozma, G. Thomas, et al.
Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors
Mol. Cancer Ther., May 1, 2008; 7(5): 1237 - 1245.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
K. H. Lu, W. Wu, B. Dave, B. M. Slomovitz, T. W. Burke, M. F. Munsell, R. R. Broaddus, and C. L. Walker
Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma
Clin. Cancer Res., May 1, 2008; 14(9): 2543 - 2550.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
N. Rhodes, D. A. Heerding, D. R. Duckett, D. J. Eberwein, V. B. Knick, T. J. Lansing, R. T. McConnell, T. M. Gilmer, S.-Y. Zhang, K. Robell, et al.
Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
Cancer Res., April 1, 2008; 68(7): 2366 - 2374.
[Abstract] [Full Text] [PDF]

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 JCOHome page
A. O'Donnell, S. Faivre, H. A. Burris III, D. Rea, V. Papadimitrakopoulou, N. Shand, H. A. Lane, K. Hazell, U. Zoellner, J. M. Kovarik, et al.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With Advanced Solid Tumors
J. Clin. Oncol., April 1, 2008; 26(10): 1588 - 1595.
[Abstract] [Full Text] [PDF]

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 JCOHome page
J. Tabernero, F. Rojo, E. Calvo, H. Burris, I. Judson, K. Hazell, E. Martinelli, S. R. y Cajal, S. Jones, L. Vidal, et al.
Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors
J. Clin. Oncol., April 1, 2008; 26(10): 1603 - 1610.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
D. Zhong, X. Liu, K. Schafer-Hales, A. I. Marcus, F. R. Khuri, S.-Y. Sun, and W. Zhou
2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition
Mol. Cancer Ther., April 1, 2008; 7(4): 809 - 817.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
P. C. McDonald, A. Oloumi, J. Mills, I. Dobreva, M. Maidan, V. Gray, E. D. Wederell, M. B. Bally, L. J. Foster, and S. Dedhar
Rictor and Integrin-Linked Kinase Interact and Regulate Akt Phosphorylation and Cancer Cell Survival
Cancer Res., March 15, 2008; 68(6): 1618 - 1624.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
D. Kong, S. Banerjee, W. Huang, Y. Li, Z. Wang, H.-R. C. Kim, and F. H. Sarkar
Mammalian Target of Rapamycin Repression by 3,3'-Diindolylmethane Inhibits Invasion and Angiogenesis in Platelet-Derived Growth Factor-D-Overexpressing PC3 Cells
Cancer Res., March 15, 2008; 68(6): 1927 - 1934.
[Abstract] [Full Text] [PDF]

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 Endocr Relat CancerHome page
A. Moreno, A. Akcakanat, M. F Munsell, A. Soni, J. C Yao, and F. Meric-Bernstam
Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors
Endocr. Relat. Cancer, March 1, 2008; 15(1): 257 - 266.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
B. Hegedus, D. Banerjee, T.-H. Yeh, S. Rothermich, A. Perry, J. B. Rubin, J. R. Garbow, and D. H. Gutmann
Preclinical Cancer Therapy in a Mouse Model of Neurofibromatosis-1 Optic Glioma
Cancer Res., March 1, 2008; 68(5): 1520 - 1528.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
S. H. Oh, Q. Jin, E. S. Kim, F. R. Khuri, and H.-Y. Lee
Insulin-like Growth Factor-I Receptor Signaling Pathway Induces Resistance to the Apoptotic Activities of SCH66336 (Lonafarnib) through Akt/Mammalian Target of Rapamycin-Mediated Increases in Survivin Expression
Clin. Cancer Res., March 1, 2008; 14(5): 1581 - 1589.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
A. A. Brandes, E. Franceschi, A. Tosoni, M. E. Hegi, and R. Stupp
Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments
Clin. Cancer Res., February 15, 2008; 14(4): 957 - 960.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
M.-E. Legrier, C.-P. H. Yang, H.-G. Yan, L. Lopez-Barcons, S. M. Keller, R. Perez-Soler, S. B. Horwitz, and H. M. McDaid
Targeting Protein Translation in Human Non Small Cell Lung Cancer via Combined MEK and Mammalian Target of Rapamycin Suppression
Cancer Res., December 1, 2007; 67(23): 11300 - 11308.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
X. Wang, P. Yue, C.-B. Chan, K. Ye, T. Ueda, R. Watanabe-Fukunaga, R. Fukunaga, H. Fu, F. R. Khuri, and S.-Y. Sun
Inhibition of Mammalian Target of Rapamycin Induces Phosphatidylinositol 3-Kinase-Dependent and Mnk-Mediated Eukaryotic Translation Initiation Factor 4E Phosphorylation
Mol. Cell. Biol., November 1, 2007; 27(21): 7405 - 7413.
[Abstract] [Full Text] [PDF]

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 JCOHome page
M. Fouladi, F. Laningham, J. Wu, M. A. O'Shaughnessy, K. Molina, A. Broniscer, S. L. Spunt, I. Luckett, C. F. Stewart, P. J. Houghton, et al.
Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors
J. Clin. Oncol., October 20, 2007; 25(30): 4806 - 4812.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
G. A. Finlay, A. J. Malhowski, Y. Liu, B. L. Fanburg, D. J. Kwiatkowski, and D. Toksoz
Selective Inhibition of Growth of Tuberous Sclerosis Complex 2 Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase Function and Reduced mTOR/S6 Kinase Activity
Cancer Res., October 15, 2007; 67(20): 9878 - 9886.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C.-H. Lu, S. L. Wyszomierski, L.-M. Tseng, M.-H. Sun, K.-H. Lan, C. L. Neal, G. B. Mills, G. N. Hortobagyi, F. J. Esteva, and D. Yu
Preclinical Testing of Clinically Applicable Strategies for Overcoming Trastuzumab Resistance Caused by PTEN Deficiency
Clin. Cancer Res., October 1, 2007; 13(19): 5883 - 5888.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
X. Q. Lun, H. Zhou, T. Alain, B. Sun, L. Wang, J. W. Barrett, M. M. Stanford, G. McFadden, J. Bell, D. L. Senger, et al.
Targeting Human Medulloblastoma: Oncolytic Virotherapy with Myxoma Virus Is Enhanced by Rapamycin
Cancer Res., September 15, 2007; 67(18): 8818 - 8827.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
E. L. Kwak, J. W. Clark, and B. Chabner
Targeted Agents: The Rules of Combination
Clin. Cancer Res., September 15, 2007; 13(18): 5232 - 5237.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
E. K. Rowinsky, H. Youssoufian, J. R. Tonra, P. Solomon, D. Burtrum, and D. L. Ludwig
IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor
Clin. Cancer Res., September 15, 2007; 13(18): 5549s - 5555s.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
Q.-W. Fan, C. K. Cheng, T. P. Nicolaides, C. S. Hackett, Z. A. Knight, K. M. Shokat, and W. A. Weiss
A Dual Phosphoinositide-3-Kinase {alpha}/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma
Cancer Res., September 1, 2007; 67(17): 7960 - 7965.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
G. J. Riely, M. G. Kris, B. Zhao, T. Akhurst, D. T. Milton, E. Moore, L. Tyson, W. Pao, N. A. Rizvi, L. H. Schwartz, et al.
Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Everolimus
Clin. Cancer Res., September 1, 2007; 13(17): 5150 - 5155.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
A. B. Hjelmeland, K. P. Lattimore, B. E. Fee, Q. Shi, S. Wickman, S. T. Keir, M. D. Hjelmeland, D. Batt, D. D. Bigner, H. S. Friedman, et al.
The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion
Mol. Cancer Ther., September 1, 2007; 6(9): 2449 - 2457.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
L. M. Ballou, E. S. Selinger, J. Y. Choi, D. G. Drueckhammer, and R. Z. Lin
Inhibition of Mammalian Target of Rapamycin Signaling by 2-(Morpholin-1-yl)pyrimido[2,1-{alpha}]isoquinolin-4-one
J. Biol. Chem., August 17, 2007; 282(33): 24463 - 24470.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
J. A. Crowell, V. E. Steele, and J. R. Fay
Targeting the AKT protein kinase for cancer chemoprevention
Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
J. D. Mosley, J. T. Poirier, D. D. Seachrist, M. D. Landis, and R. A. Keri
Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer
Mol. Cancer Ther., August 1, 2007; 6(8): 2188 - 2197.
[Abstract] [Full Text] [PDF]

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 Ann OncolHome page
I Duran, R Salazar, O Casanovas, V Arrazubi, E Vilar, L. Siu, J Yao, and J Tabernero
New drug development in digestive neuroendocrine tumors
Ann. Onc., August 1, 2007; 18(8): 1307 - 1313.
[Abstract] [Full Text] [PDF]

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 J. Nutr.Home page
T. C. Vary, G. Deiter, and C. J. Lynch
Rapamycin Limits Formation of Active Eukaryotic Initiation Factor 4F Complex Following Meal Feeding in Rat Hearts
J. Nutr., August 1, 2007; 137(8): 1857 - 1862.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
B. E. Johnson, D. Jackman, and P. A. Janne
Rationale for a Phase I Trial of Erlotinib and the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) for Patients with Relapsed Non Small Cell Lung Cancer
Clin. Cancer Res., August 1, 2007; 13(15): 4628s - 4631s.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. A. Engelman
The Role of Phosphoinositide 3-Kinase Pathway Inhibitors in the Treatment of Lung Cancer
Clin. Cancer Res., August 1, 2007; 13(15): 4637s - 4640s.
[Abstract] [Full Text] [PDF]


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