mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling

Cancer Discovery

Volumn 1, Issue 3, 2011, Pages 248-259

  Rodrik Outmezguine, Vanessa S ^a   Chandarlapaty, Sarat ^a   Pagano, Nen C ^a   Poulikakos, Poulikos I ^a   Scaltriti, Maurizio ^b   Moskatel, Elizabeth ^a   Baselga, José ^b   Guichard, Sylvie ^c   Rosen, Neal ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER   (United States)

^c ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 (4 AMINO 1 ISOPROPYL 1H PYRAZOLO [3, 4 D] PYRIMIDIN 3 YL) 1H INDOL 5 OL; 2 MORPHOLINO 8 PHENYLCHROMONE; AZD 8055; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; EVEROLIMUS; GEFITINIB; LAPATINIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE 3 PHOSPHATASE; PP 30; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; RAPAMYCIN; RIDAFOROLIMUS; TEMSIROLIMUS; TORIN1; UNCLASSIFIED DRUG;

ARTICLE; CELL DEATH; CELL PROLIFERATION; CELL SIZE; CELL SURVIVAL; DRUG TARGETING; FEEDBACK SYSTEM; HUMAN; NEOPLASM; PROTEIN CONFORMATION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION;

ANIMALS; CELL DEATH; CELL LINE, TUMOR; FEMALE; HUMANS; MICE; MICE, NUDE; MORPHOLINES; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEINS; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTOR PROTEIN-TYROSINE KINASES; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 80655126355     PISSN: 21598274     EISSN: 21598290     Source Type: Journal    
DOI: 10.1158/2159-8290.CD-11-0085     Document Type: Article

References (44)

1. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489-501.
2. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010;18:11-22.
3. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009;4:127-50.
4. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12:9-22.
5. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 2010;40:310-22.
6. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18:1926-45.
7. Tremblay F, Brule S, Hee Um S, Li Y, Masuda K, Roden M, et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrientand obesity-induced insulin resistance. Proc Natl Acad Sci U S A 2007;104:14056-61.
8. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296-302.
9. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-101.
10. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serumand glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416:375-85.
11. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 1996;15:6541-51.
12. Feldman ME, Shokat KM. New inhibitors of the PI3K-Akt-mTOR pathway: insights into mTOR signaling from a new generation of Tor Kinase Domain Inhibitors (TORKinibs). Curr Top Microbiol Immunol 2010;347:241-62.
13. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83.
14. Sparks CA, Guertin DA. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 2010;29:3733-44.
15. Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol 2000;14:783-94.
16. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-8.
17. Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996;273:239-42.
18. Agarwala SS, Case S. Everolimus (RAD001) in the treatment of advanced renal cell carcinoma: a review. Oncologist 2010;15:236-45.
19. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 2010;1804:433-9.
20. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008;5:e8.
21. Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, et al. Activation of Akt and eIF4E survival pathways by rapamycinmediated mammalian target of rapamycin inhibition. Cancer Res 2005;65:7052-8.
22. Shi Y, Yan H, Frost P, Gera J, Lichtenstein A. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 2005;4:1533-40.
23. Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 2006;10:459-72.
24. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009;284:8023-32.
25. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010;70:288-98.
26. Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 2009;69:6232-40.
27. Garcia-Martinez JM, Moran J, Clarke RG, Gray A, Cosulich SC, Chresta CM, et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 2009;421:29-42.
28. Wang X, Beugnet A, Murakami M, Yamanaka S, Proud CG. Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol 2005;25:2558-72.
29. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, et al. Hierarchical phosphorylation of the translation inhibitor 4EBP1. Genes Dev 2001;15:2852-64.
30. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-7.
31. Hresko RC, Mueckler M. mTOR. RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 2005;280: 40406-16.
32. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009;7:e38.
33. Kwon Y, Hofmann T, Montell C. Integration of phosphoinositide-and calmodulin-mediated regulation of TRPC6. Mol Cell 2007;25:491-503.
34. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007;445:437-41.
35. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011;19:58-71.
36. Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 2011;30:2547-57.
37. Fayard E, Xue G, Parcellier A, Bozulic L, Hemmings BA. Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Curr Top Microbiol Immunol 2010;346:31-56.
38. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006;11:859-71.
39. Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 2011;16 Suppl 1:12-9.
40. Sini P, James D, Chresta C, Guichard S. Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy 2010;6.
41. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231-41.
42. Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev 2008;22:1490-500.
43. She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 2005;8: 287-97.
44. She QB, Chandarlapaty S, Ye Q, Lobo J, Haskell KM, Leander KR, et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One 2008;3:e3065.