Current state of mTOR targeting in human breast cancer

Cancer Genomics and Proteomics

Volumn 11, Issue 4, 2014, Pages 167-174

  Wazir, Umar ^a,b   Wazir, Ali ^c   Khanzada, Zubair S ^d   Jiang, Wen G ^d   Sharma, Anup K ^b   Mokbel, Kefah ^a,b  

^a Princess Grace Hospital   (United Kingdom)

^b ST GEORGE'S UNIVERSITY OF LONDON   (United Kingdom)

^c AGA KHAN UNIVERSITY   (Pakistan)

^d CARDIFF UNIVERSITY   (United Kingdom)

Author keywords

Breast; Cancer; DAP1; mTOR; PIKK; Rapamycin; Review; Rictor

Indexed keywords

DEP DOMAIN CONTAINING MAMMALIAN TARGET OF RAPAMYCIN INTERACTING PROTEIN; MAMMALIAN LETHAL SEC 13 PROTEIN 8; MAMMALIAN STRESS ACTIVATED MAP KINASE INTERACTING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PROLINE RICH PROTEIN; PROTEIN OBSERVED WITH RICTOR 1; PROTEIN OBSERVED WITH RICTOR 2; RAPAMYCIN INSENSITIVE COMPANION OF MAMMALIAN TARGET OF RAPAMYCIN; REGULATORY ASSOCIATED PROTEIN OF MAMMALIAN TARGET OF RAPAMYCIN; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; CARRIER PROTEIN; MULTIPROTEIN COMPLEX; PROTEIN BINDING; PROTEIN KINASE INHIBITOR; SIGNAL PEPTIDE; TARGET OF RAPAMYCIN KINASE;

BREAST CANCER; CANCER THERAPY; CARCINOGENESIS; CLINICAL PATHWAY; HUMAN; PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; CHEMISTRY; DRUG EFFECTS; FEMALE; METABOLISM; MOLECULARLY TARGETED THERAPY; PROTEIN DOMAIN; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; BREAST NEOPLASMS; CARRIER PROTEINS; FEMALE; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MOLECULAR TARGETED THERAPY; MULTIPROTEIN COMPLEXES; PROTEIN BINDING; PROTEIN INTERACTION DOMAINS AND MOTIFS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84939445673     PISSN: 11096535     EISSN: 17906245     Source Type: Journal    
DOI: None     Document Type: Review

References (59)

1. Vezina C, Kudelski A and Sehgal SN: Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28: 721-726, 1975.
2. Sehgal SN, Baker H and Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 28: 727-732, 1975.
3. Sehgal SN: Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 31: 335-340, 1998.
4. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G and Abraham RT: Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270: 815-822, 1995.
5. Cafferkey R, McLaughlin MM, Young PR, Johnson RK and Livi GP: Yeast TOR (DRR) proteins: amino-acid sequence alignment and identification of structural motifs. Gene 141: 133-136, 1994.
6. Lovejoy CA and Cortez D: Common mechanisms of PIKK regulation. DNA Repair (Amst) 8: 1004-1008, 2009.
7. Bosotti R, Isacchi A and Sonnhammer EL: FAT: a novel domain in PIK-related kinases. Trends Biochem Sci 25: 225-227, 2000.
8. Lempiainen H and Halazonetis TD. Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J 28: 3067-3073, 2009.
9. De P, Miskimins K, Dey N and Leyland-Jones B: Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: old targets new hope. Cancer Treat Rev 39: 403- 12, 2013.
10. Bar-Peled L, Schweitzer LD, Zoncu R and Sabatini DM: Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150: 1196-1208, 2012.
11. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, Ru B and Pan D: Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4: 699-704, 2002.
12. Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO and Manning BD: TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47: 535-546, 2012.
13. Manning BD and Cantley LC: Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 28: 573-576, 2003.
14. Avruch J, Long X, Lin Y, Ortiz-Vega S, Rapley J, Papageorgiou A, Oshiro N and Kikkawa U: Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. Biochem Soc Trans 37: 223-226, 2009.
15. Yuen HF, Chan KK, Grills C, Murray JT, Platt-Higgins A, Eldin OS, O'Byrne K, Janne P, Fennell DA, Johnston PG, Rudland PS and El-Tanani M: Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clin Cancer Res 18: 380-391, 2012.
16. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO and Guan KL: TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126: 955-968, 2006.
17. Zheng M, Wang YH, Wu XN, Wu SQ, Lu BJ, Dong MQ, Zhang H, Sun P, Lin SC, Guan KL and Han J: Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energydepletion- induced suppression of mTORC1. Nat Cell Biol 13: 263-272, 2011.
18. Laplante M and Sabatini DM: mTOR signaling in growth control and disease. Cell 149: 274-293, 2012.
19. Toschi A, Lee E, Thompson S, Gadir N, Yellen P, Drain CM, Ohh M and Foster DA. Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. Cancer Lett 299: 72- 79, 2010.
20. Koren I, Reem E and Kimchi A: DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol 20: 1093-1098, 2010.
21. Wazir U, Jiang WG, Sharma AK and Mokbel K: The mRNA expression of DAP1 in human breast cancer: correlation with clinicopathological parameters. Cancer Genomics Proteomics 9: 199-201, 2012.
22. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J and Yonezawa K: Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110: 177-189, 2002.
23. Bjornsti MA and Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4: 335-348, 2004.
24. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P and Sabatini DM: GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11: 895-904, 2003.
25. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ and Sabatini DM: 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 11: 859-871, 2006.
26. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS and Sabatini DM: DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137: 873-886, 2009.
27. Hayashi T, Hatanaka M, Nagao K, Nakaseko Y, Kanoh J, Kokubu A, Ebe M and Yanagida M: Rapamycin sensitivity of the Schizosaccharomyces pombe tor2 mutant and organization of two highly phosphorylated TOR complexes by specific and common subunits. Genes Cells 12: 1357-1370, 2007.
28. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T and Mizushima N: Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 285: 20109-20116, 2010.
29. Kanoh J and Yanagida M: Tel2: a common partner of PIKrelated kinases and a link between DNA checkpoint and nutritional response? Genes Cells 12: 1301-1304, 2007.
30. Wang L, Harris TE, Roth RA and Lawrence JC Jr.: PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282: 20036-20044, 2007.
31. Jones KT, Greer ER, Pearce D and Ashrafi K: Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol 7: e60, 2009.
32. Sarbassov DD, Guertin DA, Ali SM and Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098-1101, 2005.
33. McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, Wederell ED, Bally MB, Foster LJ and Dedhar S: Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res 68: 1618-1624, 2008.
34. Mori S, Nada S, Kimura H, Tajima S, Takahashi Y, Kitamura A, Oneyama C and Okada M: The mTOR pathway controls cell proliferation by regulating the foxO3a transcription factor via SGK1 kinase. PLoS ONE 9: e88891, 2014.
35. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL and Sabatini DM: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159-68, 2006.
36. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA and Sabatini DM: mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16: 1865-70, 2006.
37. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P and Sabatini DM: Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296-302, 2004.
38. Hresko RC and Mueckler M: mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280: 40406-16, 2005.
39. Perumalsamy LR, Nagala M, Banerjee P and Sarin A: A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglect-induced death in mammalian cells. Cell Death Differ 16: 879-89, 2009.
40. Garcia-Martinez JM and Alessi DR: mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416: 375-85, 2008.
41. Lu M, Wang J, Jones KT, Ives HE, Feldman ME, Yao LJ, Shokat KM, Ashrafi K and Pearce D: mTOR complex-2 activates ENaC by phosphorylating SGK1. J Am Soc Nephrol 21: 811-818, 2010.
42. Wilkinson MG, Pino TS, Tournier S, Buck V, Martin H, Christiansen J, Wilkinson DG and Millar JB: Sin1: an evolutionarily conserved component of the eukaryotic SAPK pathway. EMBO J 18: 4210-4221, 1999.
43. Yang Q, Inoki K, Ikenoue T and Guan KL: Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20: 2820-2832, 2006.
44. Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA and Alessi DR. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 405: 513-522, 2007.
45. Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S and Griffin TJ: PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 282: 25604-25612, 2007.
46. Pearce LR, Sommer EM, Sakamoto K, Wullschleger S and Alessi DR: Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J 436: 169-79, 2011.
47. Guertin DA and Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal 2: pe24, 2009.
48. Houghton PJ: Everolimus. Clin Cancer Res 16: 1368-72, 2010.
49. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L and Motzer RJ: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356: 2271-2281, 2007.
50. Shoji K, Oda K, Kashiyama T, Ikeda Y, Nakagawa S, Sone K, Miyamoto Y, Hiraike H, Tanikawa M, Miyasaka A, Koso T, Matsumoto Y, Wada-Hiraike O, Kawana K, Kuramoto H, McCormick F, Aburatani H, Yano T, Kozuma S and Taketani Y: Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. PLoS ONE 7: e37431, 2012.
51. Noh WC, Mondesire WH, Peng J, Jian W, Zhang H, Dong J, Mills GB, Hung MC and Meric-Bernstam F: Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10: 1013-1023, 2004.
52. Gnant M: The role of mammalian target of rapamycin (mTOR) inhibition in the treatment of advanced breast cancer. Curr Oncol Rep 15: 14-23, 2013.
53. Hurvitz SA, Dalenc F, Campone M, O'Regan RM, Tjan-Heijnen VC, Gligorov J, Llombart A, Jhangiani H, Mirshahidi HR, Tan- Chiu E, Miao S, El-Hashimy M, Lincy J, Taran T, Soria JC, Sahmoud T and Andre F: A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res Treat 141: 437-446, 2013.
54. Sendur MA, Zengin N, Aksoy S and Altundag K: Everolimus: a new hope for patients with breast cancer. Curr Med Res Opin 30: 75-87, 2014.
55. Beck JT, Hortobagyi GN, Campone M, Lebrun F, Deleu I, Rugo HS, Pistilli B, Masuda N, Hart L, Melichar B, Dakhil S, Geberth M, Nunzi M, Heng DY, Brechenmacher T, El-Hashimy M, Douma S, Ringeisen F and Piccart M: Everolimus plus exemestane as first-line therapy in HR(+), HER2 (-) advanced breast cancer in BOLERO-2. Breast Cancer Res Treat 143: 459-467, 2014.
56. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, Sun Y, Neskovic-Konstantinovic Z, Guimaraes RC, Fumoleau P, Chan A, Hachemi S, Strahs A, Cincotta M, Berkenblit A, Krygowski M, Kang LL, Moore L and Hayes DF: Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 31: 195-202, 2013.
57. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaeth D, Legouffe E, Allouache D, El Kouri C and Pujade-Lauraine E: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30: 2718-2724, 2012.
58. Nelson V, Altman JK and Platanias LC: Next generation of mammalian target of rapamycin inhibitors for the treatment of cancer. Expert Opin Investig Drugs 22: 715-722, 2013.
59. Wazir U, Newbold RF, Jiang WG, Sharma AK and Mokbel K: Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer. Oncol Rep 29: 1969-1974, 2013.