Time now to TORC the TORC? New developments in mTOR pathway inhibition in lymphoid malignancies

British Journal of Haematology

Volumn 166, Issue 3, 2014, Pages 336-351

  Eyre, Toby A ^a   Collins, Graham P ^a   Goldstone, Anthony H ^b   Cwynarski, Kate ^c  

^a OXFORD UNIVERSITY HOSPITALS NHS FOUNDATION TRUST   (United Kingdom)

^b UNIVERSITY COLLEGE HOSPITAL   (United Kingdom)

^c ROYAL FREE HOSPITAL   (United Kingdom)

Author keywords

AZD2014; AZD8055; MTOR; MTORC1 2; Rapamycin

Indexed keywords

1 [4 [1 (1,4 DIOXASPIRO[4.5]DEC 8 YL) 4 (8 OXA 3 AZABICYCLO[3.2.1]OCT 3 YL) 1H PYRAZOLO[3,4 D]PYRIMIDIN 6 YL]PHENYL] 3 METHYLUREA; 2 (4 AMINO 1 ISOPROPYL 1H PYRAZOLO[3,4 D]PYRIMIDIN 3 YL) 1H INDOL 5 OL; 4 (4 AMINO 5 (7 METHOXY 1H INDOL 2 YL)IMIDAZO[5,1 F][1,2,4]TRIAZIN 7 YL)CYCLOHEXANECARBOXYLIC ACID; AZD 2014; AZD 8055; CISPLATIN; CYTARABINE; DACTOLISIB; DEPTOR INHIBITOR; DEXAMETHASONE; EVEROLIMUS; FK 506 BINDING PROTEIN; HISTONE DEACETYLASE INHIBITOR; INITIATION FACTOR 4E; INITIATION FACTOR 4E BINDING PROTEIN 1; INK 128; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MLN 0128; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE 3 KINASE; PLATELET DERIVED GROWTH FACTOR; PROTEIN KINASE B; RAPAMYCIN; RITUXIMAB; S6 KINASE; SOMATOMEDIN; TEMSIROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANEMIA; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; ASTHENIA; AUTOLOGOUS STEM CELL TRANSPLANTATION; BONE MARROW SUPPRESSION; CANCER CELL LINE; CANCER INHIBITION; CANCER RESISTANCE; CARCINOGENESIS; CCND1 GENE; CELL CYCLE ARREST; CELL ENERGY; CELL PROLIFERATION; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC LYMPHOCYTIC LYMPHOMA; CUTANEOUS T CELL LYMPHOMA; DEPLETION; DNA DAMAGE; DRUG BIOAVAILABILITY; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG FATALITY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; EDEMA; ENZYME ACTIVATION; GENE; HEMATOLOGIC MALIGNANCY; HEMATOPOIETIC CELL; HODGKIN DISEASE; HUMAN; HYPERLIPIDEMIA; HYPERTENSION; IN VITRO STUDY; IN VIVO STUDY; LARGE CELL LYMPHOMA; LUNG TOXICITY; LYMPHOCYTOMA; LYMPHOMA; MAINTENANCE THERAPY; MANTLE CELL LYMPHOMA; MULTIPLE CYCLE TREATMENT; NEUTROPENIA; NONHODGKIN LYMPHOMA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; SIGNAL TRANSDUCTION; T CELL LYMPHOMA; THROMBOCYTOPENIA; TREATMENT DURATION; TREATMENT RESPONSE; WALDENSTROEM MACROGLOBULINEMIA;

AZD2014; AZD8055; MTOR; MTORC1/2; RAPAMYCIN;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; LEUKEMIA, T-CELL; LYMPHOMA, T-CELL; MULTIPROTEIN COMPLEXES; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84904046672     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.12945     Document Type: Article

References (134)

1. Aguirre, V., Werner, E.D., Giraud, J., Lee, Y.H., Shoelson, S.E. & White, M.F. (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. The Journal of Biological Chemistry, 277, 1531-1537.
2. Aleskog, A., Norberg, M., Nygren, P., Rickardson, L., Kanduri, M., Tobin, G., Aberg, M., Gustafsson, M.G., Rosenquist, R. & Lindhagen, E. (2008) Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination. Leukemia & Lymphoma, 49, 2333-2343.
3. Altman, J.K., Sassano, A., Kaur, S., Glaser, H., Kroczynska, B., Redig, A.J., Russo, S., Barr, S. & Platanias, L.C. (2011) Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 17, 4378-4388.
4. Alyea, E.P., Li, S., Kim, H.T., Cutler, C., Ho, V., Soiffer, R.J. & Antin, J.H. (2008) Sirolimus, tacrolimus, and low-dose methotrexate as graft-versus-host disease prophylaxis in related and unrelated donor reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation, 14, 920-926.
5. Ansell, S.M., Inwards, D.J., Rowland, K.M., Flynn, P.J., Morton, R.F., Moore, D.F., Kaufmann, S.H., Ghobrial, I., Kurtin, P.J., Maurer, M., Allmer, C. & Witzig, T.E. (2008) Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer, 3, 508-514.
6. Ansell, S.M., Tang, H., Kurtin, P.J., Koenig, P.A., Inwards, D.J., Shah, K., Ziesmer, S.C., Feldman, A.L., Rao, R., Gupta, M., Erlichman, C. & Witzig, T.E. (2011) Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncology, 4, 361-368.
7. Asahina, H., Nokihara, H., Yamamoto, N., Yamada, Y., Tamura, Y., Honda, K., Seki, Y., Tanabe, Y., Shimada, H., Shi, X. & Tamura, T. (2012) Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study. Investigational New Drugs, 3, 677-684.
8. Banerji, U., Dean, E. & Gonzalez, M. (2012) First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors. Journal of Clinical Oncology, 30 (suppl 3004).
9. Barnes, J.A., Jacobsen, E., Feng, Y., Freedman, A., Hochberg, E.P., Lacasce, A.S., Armand, P., Joyce, R., Sohani, A.R., Rodig, S.J., Neuberg, D., Fisher, D.C. & Abramson, J.S. (2013) Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma. Haematologica, 98, 615-619.
10. Baumann, P., Mandl-Weber, S., Oduncu, F. & Schmidmaier, R. (2009) The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Experimental Cell Research, 315, 485-497.
11. Baumann, P., Schneider, L., Mandl-Weber, S., Oduncu, F. & Schmidmaier, R. (2012) Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma. Anti-Cancer Drugs, 23, 131-138.
12. Becker, M.N., Wu, K.J., Marlow, L.A., Kreinest, P.A., Vonroemeling, C.A., Copland, J.A. & Williams, C.R. (2013) The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro. Urologic Oncology, 3, 317-326.
13. Bhagwat, S.V., Gokhale, P.C., Crew, A.P., Cooke, A., Yao, Y., Mantis, C., Kahler, J., Workman, J., Bittner, M., Dudkin, L., Epstein, D.M., Gibson, N.W., Wild, R., Arnold, L.D., Houghton, P.J. & Pachter, J.A. (2011) Preclinical characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Molecular Cancer Therapeutics, 10, 1394-1406.
14. Bracho-Valdés, I., Moreno-Alvarez, P., Valencia-Martínez, I., Robles-Molina, E., Chávez-Vargas, L. & Vázquez-Prado, J. (2011) mTORC1- and mTORC2-interacting proteins keep their multifunctional partners focused. IUBMB Life, 63, 896-914.
15. Byrd, J.C., Furman, R.R., Coutre, S.E., Flinn, I.W., Burger, J.A., Blum, K.A., Grant, B., Sharman, J.P., Coleman, M., Wierda, W.G., Jones, J.A., Zhao, W., Heerema, N.A., Johnson, A.J., Sukbuntherng, J., Chang, B.Y., Clow, F., Hedrick, E., Buggy, J.J., James, D.F. & O'Brien, S. (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. The New England Journal of Medicine, 369, 32-42.
16. Cantley, L.C. (2002) The phosphoinositide 3-kinase pathway. Science (New York, N.Y.), 296, 1655-1657.
17. Carayol, N., Vakana, E., Sassano, A., Kaur, S., Goussetis, D.J., Glaser, H., Druker, B.J., Donato, N.J., Altman, J.K., Barr, S. & Platanias, L.C. (2010) Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proceedings of the National Academy of Sciences of the United States of America, 107, 12469-12474.
18. 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. (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. The Journal of Clinical Investigation, 118, 3065-3074.
19. Chan, S.M., Weng, A.P., Tibshirani, R., Aster, J.C. & Utz, P.J. (2007) Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood, 110, 278-286.
20. Chiang, G.G. & Abraham, R.T. (2007) Targeting the mTOR signaling network in cancer. Trends in Molecular Medicine, 13, 433-442.
21. Chresta, C.M., Davies, B.R., Hickson, I., Harding, T., Cosulich, S., Critchlow, S.E., Vincent, J.P., Ellston, R., Jones, D., Sini, P., James, D., Howard, Z., Dudley, P., Hughes, G., Smith, L., Maguire, S., Hummersone, M., Malagu, K., Menear, K., Jenkins, R., Jacobsen, M., Smith, G.C., Guichard, S. & Pass, M. (2010) 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 Research, 70, 288-298.
22. Chumsri, S., Zhao, M., Garofalo, M., Burger, A., Hamburger, A., Zhao, F. & Rapoport, A. (2008) Inhibition of the mammalian target of rapamycin (mTOR) in a case of refractory primary cutaneous anaplastic large cell lymphoma. Leukemia & Lymphoma, 49, 359-361.
23. Civallero, M., Cosenza, M., Marcheselli, L., Pozzi, S. & Sacchi, S. (2012) NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy. Expert Opinion on Investigational Drugs, 21, 1597-1606.
24. Dal Col, J., Zancai, P., Terrin, L., Guidoboni, M., Ponzoni, M., Pavan, A., Spina, M., Bergamin, S., Rizzo, S., Tirelli, U., De Rossi, A., Doglioni, C. & Dolcetti, R. (2008) Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood, 111, 5142-5151.
25. Decker, T., Sandherr, M., Goetze, K., Oelsner, M., Ringshausen, I. & Peschel, C. (2009) A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL. Annals of Hematology, 3, 221-227.
26. Dong, L.H., Cheng, S., Zheng, Z., Wang, L., Shen, Y., Shen, Z.X., Chen, S.J. & Zhao, W.L. (2013) Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma. Journal of Hematology & Oncology, 6, 53.
27. Dutton, A., Reynolds, G.M., Dawson, C.W., Young, L.S. & Murray, P.G. (2005) Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR. The Journal of Pathology, 205, 498-506.
28. Easton, J.B. & Houghton, P.J. (2006) mTOR and cancer therapy. Oncogene, 25, 6436-6446.
29. Efeyan, A. & Sabatini, D.M. (2010) mTOR and cancer: many loops in one pathway. Current Opinion in Cell Biology, 22, 169-176.
30. Ellard, S.L., Clemons, M., Gelmon, K.A., Norris, B., Kennecke, H., Chia, S., Pritchard, K., Eisen, A., Vandenberg, T., Taylor, M., Sauerbrei, E., Mishaeli, M., Huntsman, D., Walsh, W., Olivo, M., McIntosh, L. & Seymour, L. (2009) Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. Journal of Clinical Oncolology, 27, 4536-4544.
31. Feng, Z., Zhang, H., Levine, A.J. & Jin, S. (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proceedings of the National Academy of Sciences of the United States of America, 102, 8204-8209.
32. Fingar, D.C. & Blenis, J. (2004) Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene, 23, 3151-3171.
33. Flinn, I.W., Kahl, B.S., Leonard, J.P., Furman, R.R., Brown, J.R., Byrd, J.C., Wagner-Johnston, N.D., Coutre, S.E., Benson, D.M., Peterman, S., Cho, Y., Webb, H.K., Johnson, D.M., Yu, A.S., Ulrich, R.G., Godfrey, W.R., Miller, L.L. & Spurgeon, S.E. (2014) Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood, doi: 10.1182/blood-2013-11-538546.
34. Furman, R.R., Sharman, J.P., Coutre, S.E., Cheson, B.D., Pagel, J.M., Hillmen, P., Barrientos, J.C., Zelenetz, A.D., Kipps, T.J., Flinn, I., Ghia, P., Eradat, H., Ervin, T., Lamanna, N., Coiffier, B., Pettitt, A.R., Ma, S., Stilgenbauer, S., Cramer, P., Aiello, M., Johnson, D.M., Miller, L.L., Li, D., Jahn, T.M., Dansey, R.D., Hallek, M. & O'Brien, S.M. (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. New England Journal of Medicine, 370, 997-1007.
35. Geisler, C.H., Kolstad, A., Laurell, A., Andersen, N.S., Pedersen, L.B., Jerkeman, M., Eriksson, M., Nordström, M., Kimby, E., Boesen, A.M., Kuittinen, O., Lauritzsen, G.F., Nilsson-Ehle, H., Ralfkiaer, E., Akerman, M., Ehinger, M., Sundström, C., Langholm, R., Delabie, J., Karjalainen-Lindsberg, M.-L., Brown, P & Elonen, E; Nordic Lymphoma Group. (2008) Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood, 7, 2687-2693.
36. Georgakis, G., Yazbeck, V., Li, Y. & Younes, A. (2006) Preclinical rationale for therapeutic targeting of mTOR by CC-I779 and rapamycin in Hodgkin lymphoma. Journal of Clinical Oncology, 24, 10070.
37. Ghielmini, M., Schmitz, S.F., Bürki, K., Pichert, G., Betticher, D.C., Stupp, R., Wernli, M., Lohri, A., Schmitter, D., Bertoni, F. & Cerny, T. (2000) The effect of Rituximab on patients with follicular and mantle-cell lymphoma. Swiss Group for Clinical Cancer Research (SAKK). Annals of Oncology, 11, 123-126.
38. Ghobrial, I.M., Gertz, M., Laplant, B., Camoriano, J., Hayman, S., Lacy, M., Chuma, S., Harris, B., Leduc, R., Rourke, M., Ansell, S.M., Deangelo, D., Dispenzieri, A., Bergsagel, L., Reeder, C., Anderson, K.C., Richardson, P.G., Treon, S.P. & Witzig, T.E. (2010) Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. Journal of Clinical Oncology, 8, 1408-1414.
39. Gingras, A.C., Gygi, S.P., Raught, B., Polakiewicz, R.D., Abraham, R.T., Hoekstra, M.F., Aebersold, R. & Sonenberg, N. (1999) Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes & Development, 13, 1422-1437.
40. Gladden, A.B., Woolery, R., Aggarwal, P., Wasik, M.A. & Diehl, J.A. (2006) Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene, 25, 998-1007.
41. Golay, J., Zaffaroni, L., Vaccari, T., Lazzari, M., Borleri, G.M., Bernasconi, S., Tedesco, F., Rambaldi, A. & Introna, M. (2000) Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood, 95, 3900-3908.
42. Gopal, A.K., Kahl, B.S., de Vos, S., Wagner-Johnston, N.D., Schuster, S.J., Jurczak, W.J., Flinn, I.W., Flowers, C.R., Martin, P., Viardot, A., Blum, K. A, Goy, A.H., Davies, A.J., Zinzani, P.L., Dreyling, M., Johnson, D., Miller, L.L., Holes, L., Li, D., Dansey, R.D., Godfrey, W.R. & Salles, G.A. (2014) PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma. The New England Journal of Medicine, 11, 1008-1018.
43. Grolleau, A., Bowman, J., Pradet-Balade, B., Puravs, E., Hanash, S., Garcia-Sanz, J.A. & Beretta, L. (2002) Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. The Journal of Biological Chemistry, 277, 22175-22184.
44. Guichard, S., Howard, Z. & Heathcote, D. (2012) AZD2014, a dual mTORC1 and mTORC2 inhibitor is differentiated from allosteric inhibitors of mTORC1 in ER+ breast cancer. Cancer Research, 72(Suppl. 1).
45. Gupta, M., Ansell, S.M., Novak, A.J., Kumar, S., Kaufmann, S.H. & Witzig, T.E. (2009) Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood, 114, 2926-2935.
46. Gupta, M., Hendrickson, A.E.W., Yun, S.S., Han, J.J., Schneider, P.A., Koh, B.D., Stenson, M.J., Wellik, L.E., Shing, J.C., Peterson, K.L., Flatten, K.S., Hess, A.D., Smith, B.D., Karp, J.E., Barr, S., Witzig, T.E. & Kaufmann, S.H. (2012) Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. Blood, 119, 476-487.
47. Haritunians, T., Mori, A., O'Kelly, J., Luong, Q.T., Giles, F.J. & Koeffler, H.P. (2007) Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 21, 333-339.
48. Hay, N. & Sonenberg, N. (2004) Upstream and downstream of mTOR. Genes & Development, 18, 1926-1945.
49. Hess, G., Herbrecht, R., Romaguera, J., Verhoef, G., Crump, M., Gisselbrecht, C., Laurell, A., Offner, F., Strahs, A., Berkenblit, A., Hanushevsky, O., Clancy, J., Hewes, B., Moore, L. & Coiffier, B. (2009) Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. Journal of Clinical Oncology, 23, 3822-3829.
50. Hipp, S., Ringshausen, I., Oelsner, M., Bogner, C., Peschel, C. & Decker, T. (2005) Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica, 90, 1433-1434.
51. Hoang, B., Benavides, A., Shi, Y., Yang, Y., Frost, P., Gera, J. & Lichtenstein, A. (2012) The PP242 mammalian target of rapamycin (mTOR) inhibitor activates extracellular signal-regulated kinase (ERK) in multiple myeloma cells via a target of rapamycin complex 1 (TORC1)/eukaryotic translation initiation factor 4E (eIF-4E)/RAF pathway and activ. The Journal of Biological Chemistry, 287, 21796-21805.
52. Holz, M.K., Ballif, B.A., Gygi, S.P. & Blenis, J. (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell, 123, 569-580.
53. Hsu, P.P., Kang, S.A., Rameseder, J., Zhang, Y., Ottina, K.A., Lim, D., Peterson, T.R., Choi, Y., Gray, N.S., Yaffe, M.B., Marto, J.A. & Sabatini, D.M. (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science (New York, N.Y.), 332, 1317-1322.
54. Huang, J., Dibble, C.C., Matsuzaki, M. & Manning, B.D. (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Molecular and Cellular Biology, 28, 4104-4115.
55. Huang, J., Wu, S., Wu, C.-L. & Manning, B.D. (2009) Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Research, 69, 6107-6114.
56. Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Rüegg, M.A., Hall, A. & Hall, M.N. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biology, 6, 1122-1128.
57. Janes, M.R., Vu, C., Mallya, S., Shieh, M.P., Limon, J.J., Li, L.-S., Jessen, K.A., Martin, M.B., Ren, P., Lilly, M.B., Sender, L.S., Liu, Y., Rommel, C. & Fruman, D.A. (2013) Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. Leukemia, 27, 586-594.
58. Jazirehi, A.R., Vega, M.I., Chatterjee, D., Goodglick, L. & Bonavida, B. (2004) Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. Cancer Research, 64, 7117-7126.
59. Jemal, A., Siegel, R., Xu, J. & Ward, E. (2010) Cancer statistics. CA: A Cancer Journal for Clinicians, 60, 277-300.
60. Johnston, P.B., Inwards, D.J., Colgan, J.P., Laplant, B.R., Kabat, B.F., Habermann, T.M., Micallef, I.N., Porrata, L.F., Ansell, S.M., Reeder, C.B., Roy, V. & Witzig, T.E. (2010) A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. American Journal of Hematology, 5, 320-324.
61. Jundt, F., Raetzel, N., Müller, C., Calkhoven, C.F., Kley, K., Mathas, S., Lietz, A., Leutz, A. & Dörken, B. (2005) A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein beta and NF-κB activity in Hodgkin and anaplastic large cell lymphomas. Blood, 106, 1801-1807.
62. Kampa-Schittenhelm, K.M., Heinrich, M.C., Akmut, F., Rasp, K.H., Illing, B., Döhner, H., Döhner, K. & Schittenhelm, M.M. (2013) Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia. Molecular Cancer, 12, 46.
63. Kim, D.-H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P. & Sabatini, D.M. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110, 163-175.
64. Kim, A., Park, S., Lee, J.-E., Jang, W.-S., Lee, S.-J., Kang, H.J. & Lee, S.-S. (2012) The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells. Leukemia Research, 36, 912-920.
65. Klos, K.S., Wyszomierski, S.L., Sun, M., Tan, M., Zhou, X., Li, P., Yang, W., Yin, G., Hittelman, W.N. & Yu, D. (2006) ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Research, 66, 2028-2037.
66. Kluin-Nelemans, H.C., Hoster, E., Hermine, O., Walewski, J., Trneny, M., Geisler, C.H., Stilgenbauer, S., Thieblemont, C., Vehling-Kaiser, U., Doorduijn, J.K., Coiffier, B., Forstpointner, R., Tilly, H., Kanz, L., Feugier, P., Szymczyk, M., Hallek, M., Kremers, S., Lepeu, G., Sanhes, L., Zijlstra, J.M., Bouabdallah, R., Lugtenburg, P.J., Macro, M., Pfreundschuh, M., Procházka, V., Di Raimondo, F., Ribrag, V., Uppenkamp, M., André, M., Klapper, W., Hiddemann, W., Unterhalt, M. & Dreyling, M.H. (2012) Treatment of older patients with mantle-cell lymphoma. New England Journal of Medicine, 367, 520-531.
67. Leleu, X., Jia, X., Runnels, J., Ngo, H.T., Moreau, A.-S., Farag, M., Spencer, J.A., Pitsillides, C.M., Hatjiharissi, E., Roccaro, A., O'Sullivan, G., McMillin, D.W., Moreno, D., Kiziltepe, T., Carrasco, R., Treon, S.P., Hideshima, T., Anderson, K.C., Lin, C.P. & Ghobrial, I.M. (2007) The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia. Blood, 110, 4417-4426.
68. Leseux, L., Hamdi, S.M., Al Saati, T., Capilla, F., Recher, C., Laurent, G. & Bezombes, C. (2006) Syk-dependent mTOR activation in follicular lymphoma cells. Blood, 108, 4156-4162.
69. Li, H., Lin, J., Wang, X., Yao, G., Wang, L., Zheng, H., Yang, C., Jia, C., Liu, A. & Bai, X. (2012) Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer. Breast Cancer Research and Treatment, 134, 1057-1066.
70. Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J.L., Bonenfant, D., Oppliger, W., Jenoe, P. & Hall, M.N. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular Cell, 10, 457-468.
71. Lukas, J., Jadayel, D., Bartkova, J., Nacheva, E., Dyer, M.J., Strauss, M. & Bartek, J. (1994) BCL-1/cyclin D1 oncoprotein oscillates and subverts the G1 phase control in B-cell neoplasms carrying the t(11;14) translocation. Oncogene, 9, 2159-2167.
72. Mahalingam, M. & Cooper, J.A. (2001) Phosphorylation of mammalian eIF4E by Mnk1 and Mnk2: tantalizing prospects for a role in translation. Progress in Molecular and Subcellular Biology, 27, 132-142.
73. Maiso, P., Liu, Y., Morgan, B., Azab, A.K., Ren, P., Martin, M.B., Zhang, Y., Liu, Y., Sacco, A., Ngo, H., Azab, F., Quang, P., Rodig, S.J., Lin, C.P., Roccaro, A.M., Rommel, C. & Ghobrial, I.M. (2011) Defining the role of TORC1/2 in multiple myeloma. Blood, 118, 6860-6870.
74. Mallya, S., Fitch, B.A., Lee, J.S., So, L., Janes, M.R. & Fruman, D.A. (2014) Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1. PLoS One, 9, e88865.
75. Manning, B.D. & Cantley, L.C. (2007) AKT/PKB signaling: navigating downstream. Cell, 129, 1261-1274.
76. Márk, A., Hajdu, M., Váradi, Z., Sticz, T.B., Nagy, N., Csomor, J., Berczi, L., Varga, V., Csóka, M., Kopper, L. & Sebestyén, A. (2013) Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease - a combined tissue microarray, in vitro and in vivo study. BMC Cancer, 13, 250.
77. Markman, B., Tabernero, J., Krop, I., Shapiro, G.I., Siu, L., Chen, L.C., Mita, M., Melendez Cuero, M., Stutvoet, S., Birle, D., Anak, O., Hackl, W. & Baselga, J. (2012) Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, 23, 2399-2408.
78. Marzec, M., Kasprzycka, M., Liu, X., El-Salem, M., Halasa, K., Raghunath, P.N., Bucki, R., Wlodarski, P. & Wasik, M.A. (2007) Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene, 26, 5606-5614.
79. Marzec, M., Liu, X., Kasprzycka, M., Witkiewicz, A., Raghunath, P.N., El-Salem, M., Robertson, E., Odum, N. & Wasik, M.A. (2008) IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes. Blood, 111, 2181-2189.
80. Marzec, M., Liu, X., Wysocka, M., Rook, A.H., Odum, N. & Wasik, M.A. (2011) Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells. PLoS One, 6, e24849.
81. McCubrey, J.A., Steelman, L.S., Abrams, S.L., Bertrand, F.E., Ludwig, D.E., Bäsecke, J., Libra, M., Stivala, F., Milella, M., Tafuri, A., Lunghi, P., Bonati, A. & Martelli, A.M. (2008) Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 22, 708-722.
82. Mohi, M.G., Boulton, C., Gu, T.-L., Sternberg, D.W., Neuberg, D., Griffin, J.D., Gilliland, D.G. & Neel, B.G. (2004) Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proceedings of the National Academy of Sciences of the United States of America, 101, 3130-3135.
83. Motzer, R.J., Escudier, B., Oudard, S., Hutson, T.E., Porta, C., Bracarda, S., Grünwald, V., Thompson, J.A., Figlin, R.A., Hollaender, N., Urbanowitz, G., Berg, W.J., Kay, A., Lebwohl, D. & Ravaud, A. (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet, 9637, 449-456.
84. Müller, A., Zang, C., Chumduri, C., Dörken, B., Daniel, P.T. & Scholz, C.W. (2013) Concurrent inhibition of PI3K and mTORC1/mTORC2 overcomes resistance to rapamycin induced apoptosis by down-regulation of Mcl-1 in mantle cell lymphoma. International Journal of Cancer. Journal International du Cancer, 133, 1813-1824.
85. Naing, A., Aghajanian, C., Raymond, E., Olmos, D., Schwartz, G., Oelmann, E., Grinsted, L., Burke, W., Taylor, R., Kaye, S., Kurzrock, R. & Banerji, U. (2012) Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. British Journal of Cancer, 107, 1093-1099.
86. Nasu, R., Nannya, Y., Shinohara, A., Ichikawa, M. & Kurokawa, M. (2014) Favorable outcomes of tacrolimus compared with cyclosporine A for GVHD prophylaxis in HSCT for standard-risk hematological diseases. Annals of Hematology, doi: 10.1007/s00277-014-2027-y.
87. O'Reilly, T. & McSheehy, P.M. (2010) Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals. Translational Oncology, 3, 65-79.
88. 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. (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Research, 66, 1500-1508.
89. Peponi, E., Drakos, E., Reyes, G., Leventaki, V., Rassidakis, G.Z. & Medeiros, L.J. (2006) Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. The American Journal of Pathology, 169, 2171-2180.
90. Peterson, T.R., Laplante, M., Thoreen, C.C., Sancak, Y., Kang, S.A., Kuehl, W.M., Gray, N.S. & Sabatini, D.M. (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 137, 873-886.
91. Petrich, A.M., Leshchenko, V., Kuo, P.-Y., Xia, B., Thirukonda, V.K., Ulahannan, N., Gordon, S., Fazzari, M.J., Ye, B.H., Sparano, J.A. & Parekh, S. (2012) Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma. Clinical Cancer Research, 18, 2534-2544.
92. Pike, K.G., Malagu, K., Hummersone, M.G., Menear, K. & a, Duggan, H.M.E., Gomez, S., Martin, N.M.B., Ruston, L., Pass, S.L. & Pass, M., (2013) Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorganic & Medicinal Chemistry Letters, 23, 1212-1216.
93. Renner, C., Zinzani, P.L., Gressin, R., Klingbiel, D., Dietrich, P.-Y., Hitz, F., Bargetzi, M., Mingrone, W., Martinelli, G., Trojan, A., Bouabdallah, K., Lohri, A., Gyan, E., Biaggi, C., Cogliatti, S., Bertoni, F., Ghielmini, M., Brauchli, P. & Ketterer, N. (2012) A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica, 97, 1085-1091.
94. Richardson, C.J., Schalm, S.S. & Blenis, J. (2004) PI3-kinase and TOR: PIKTORing cell growth. Seminars in Cell & Developmental Biology, 15, 147-159.
95. Roccaro, A.M., Sacco, A., Husu, E.N., Pitsillides, C., Vesole, S., Azab, A.K., Azab, F., Melhem, M., Ngo, H.T., Quang, P., Maiso, P., Runnels, J., Liang, M.-C., Wong, K.-K., Lin, C. & Ghobrial, I.M. (2010) Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia. Blood, 115, 559-569.
96. Romaguera, J.E., Fayad, L., Rodriguez, M.A., Broglio, K.R., Hagemeister, F.B., Pro, B., McLaughlin, P., Younes, A., Samaniego, F., Goy, A., Sarris, A.H., Dang, N.H., Wang, M., Beasley, V., Medeiros, L.J., Katz, R.L., Gagneja, H., Samuels, B.I., Smith, T.L. & Cabanillas, F.F. (2005) High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. Journal of Clinical Oncology, 28, 7013-7023.
97. Rosenwald, I.B., Kaspar, R., Rousseau, D., Gehrke, L., Leboulch, P., Chen, J.J., Schmidt, E.V., Sonenberg, N. & London, I.M. (1995) Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. The Journal of Biological Chemistry, 270, 21176-21180.
98. Rudelius, M., Pittaluga, S., Nishizuka, S., Pham, T.H.-T., Fend, F., Jaffe, E.S., Quintanilla-Martinez, L. & Raffeld, M. (2006) Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood, 108, 1668-1676.
99. Sakata, A., Kuwahara, K., Ohmura, T., Inui, S. & Sakaguchi, N. (1999) Involvement of a rapamycin-sensitive pathway in CD40-mediated activation of murine B cells in vitro. Immunology Letters, 68, 301-309.
100. Sarbassov, D.D., Ali, S.M., Kim, D.-H., Guertin, D.A., Latek, R.R., Erdjument-Bromage, H., Tempst, P. & Sabatini, D.M. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current Biology: CB, 14, 1296-1302.
101. Sarbassov, D.D., Guertin, D.A., Ali, S.M. & Sabatini, D.M. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (New York, N.Y.), 307, 1098-1101.
102. Sarbassov, D.D., Ali, S.M., Sengupta, S., Sheen, J.-H., Hsu, P.P., Bagley, A.F., Markhard, A.L. & Sabatini, D.M. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell, 22, 159-168.
103. Scheid, M.P. & Woodgett, J.R. (2001) PKB/AKT: functional insights from genetic models. Nature Reviews. Molecular Cell Biology, 2, 760-768.
104. Schmelzle, T. & Hall, M.N. (2000) TOR, a central controller of cell growth. Cell, 103, 253-262.
105. Sengupta, S., Peterson, T.R. & Sabatini, D.M. (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Molecular Cell, 40, 310-322.
106. Shahbazian, D., Roux, P.P., Mieulet, V., Cohen, M.S., Raught, B., Taunton, J., Hershey, J.W.B., Blenis, J., Pende, M. & Sonenberg, N. (2006) The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. The EMBO Journal, 25, 2781-2791.
107. Shan, D., Ledbetter, J.A. & Press, O.W. (2000) Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunology, Immunotherapy: CII, 48, 673-683.
108. Sini, P., James, D., Chresta, C. & Guichard, S. (2010) Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy, 6, 553-554.
109. Smith, S.M., van Besien, K., Karrison, T., Dancey, J., McLaughlin, P., Younes, A., Smith, S., Stiff, P., Lester, E., Modi, S., Doyle, L.A., Vokes, E.E. & Pro, B. (2010) Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. Journal of Clinical Oncology, 31, 4740-4746.
110. Sparks, C.A. & Guertin, D.A. (2010) Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene, 29, 3733-3744.
111. Swords, R., Kelly, K., Carew, J., Nawrocki, S., Mahalingam, D., Sarantopoulos, J., Bearss, D. & Giles, F. (2011) The Pim kinases: new targets for drug development. Current Drug Targets, 12, 2059-2066.
112. Tan, D. & Dumez, H. (2010) in-human phase I study exploring three schedules of OSI-027, a novel small molecule TORC1/TORC2 inhibitor, in patients with advanced solid tumors and lymphoma. Journal of Clinical Oncology (ASCO Meeting Abstracts), 28, 3006.
113. Thomas, G.V. (2006) mTOR and cancer: reason for dancing at the crossroads? Current Opinion in Genetics & Development, 16, 78-84.
114. Vega, F., Medeiros, L.J., Leventaki, V., Atwell, C., Cho-Vega, J.H., Tian, L., Claret, F.-X. & Rassidakis, G.Z. (2006) Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Research, 66, 6589-6597.
115. Vézina, C., Kudelski, A. & Sehgal, S.N. (1975) Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. The Journal of Antibiotics, 28, 721-726.
116. Wang, S., Rosenwald, I.B., Hutzler, M.J., Pihan, G.A., Savas, L., Chen, J.J. & Woda, B.A. (1999) Expression of the eukaryotic translation initiation factors 4E and 2alpha in non-Hodgkin's lymphomas. The American Journal of Pathology, 155, 247-255.
117. Wang, X., Yue, P., Chan, C.-B., Ye, K., Ueda, T., Watanabe-Fukunaga, R., Fukunaga, R., Fu, H., Khuri, F.R. & Sun, S.-Y. (2007) Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Molecular and Cellular Biology, 27, 7405-7413.
118. Wanner, K., Hipp, S., Oelsner, M., Ringshausen, I., Bogner, C., Peschel, C. & Decker, T. (2006) Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. British Journal of Haematology, 134, 475-484.
119. Webster, A.C., Lee, V.W., Chapman, J.R. & Craig, J.C. (2006) Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database of Systematic Reviews (Online), CD004290.
120. Willems, L., Chapuis, N., Puissant, A., Maciel, T.T., Green, A.S., Jacque, N., Vignon, C., Park, S., Guichard, S., Herault, O., Fricot, A., Hermine, O., Moura, I.C., Auberger, P., Ifrah, N., Dreyfus, F., Bonnet, D., Lacombe, C., Mayeux, P., Bouscary, D. & Tamburini, J. (2012) The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia, 26, 1195-1202.
121. Wilson, W., Gerecitano, J. & Goy, A. (2012) The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large. Blood, 120, abstract 686.
122. Witzens-Harig, M., Memmer, M.L., Dreyling, M. & Hess, G. (2013) A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large ce. BMC Cancer, 13, 308.
123. Witzig, T.E. & Gupta, M. (2010) Signal transduction inhibitor therapy for lymphoma. Hematology/the Education Program of the American Society of Hematology. American Society of Hematology. Education Program, 2010, 265-270.
124. Witzig, T.E., Geyer, S.M., Ghobrial, I., Inwards, D.J., Fonseca, R., Kurtin, P., Ansell, S.M., Luyun, R., Flynn, P.J., Morton, R.F., Dakhil, S.R., Gross, H. & Kaufmann, S.H. (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 23, 5347-5356.
125. Witzig, T.E., Reeder, C.B., LaPlant, B.R., Gupta, M., Johnston, P.B., Micallef, I.N., Porrata, L.F., Ansell, S.M., Colgan, J.P., Jacobsen, E.D., Ghobrial, I.M. & Habermann, T.M. (2011) A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia, 2, 341-347.
126. Wlodarski, P., Kasprzycka, M., Liu, X., Marzec, M., Robertson, E.S., Slupianek, A. & Wasik, M.A. (2005) Activation of mammalian target of rapamycin in transformed B lymphocytes is nutrient dependent but independent of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, insulin growth factor-I, and serum. Cancer Research, 65, 7800-7808.
127. Würflein, D., Dechant, M., Stockmeyer, B., Tutt, A.L., Hu, P., Repp, R., Kalden, J.R., van de Winkel, J.G., Epstein, A.L., Valerius, T., Glennie, M. & Gramatzki, M. (1998) Evaluating antibodies for their capacity to induce cell-mediated lysis of malignant B cells. Cancer Research, 58, 3051-3058.
128. Xu, Z.-Z., Xia, Z.-G., Wang, A.-H., Wang, W.-F., Liu, Z.-Y., Chen, L.-Y. & Li, J.-M. (2013) Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: clinical significance and inhibitory effect of rituximab. Annals of Hematology, 92, 1351-1358.
129. Yazbeck, V.Y., Buglio, D., Georgakis, G.V., Li, Y., Iwado, E., Romaguera, J.E., Kondo, S. & Younes, A. (2008) Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Experimental Hematology, 36, 443-450.
130. Yu, K., Shi, C., Toral-Barza, L., Lucas, J., Shor, B., Kim, J.E., Zhang, W.-G., Mahoney, R., Gaydos, C., Tardio, L., Kim, S.K., Conant, R., Curran, K., Kaplan, J., Verheijen, J., Ayral-Kaloustian, S., Mansour, T.S., Abraham, R.T., Zask, A. & Gibbons, J.J. (2010) Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Research, 70, 621-631.
131. Zang, C., Eucker, J., Liu, H., Müller, A., Possinger, K. & Scholz, C.W. (2013) Concurrent inhibition of PI3-kinase and mTOR induces cell death in diffuse large B cell lymphomas, a mechanism involving down regulation of Mcl-1. Cancer Letters, 339, 288-297.
132. Zeng, Z., Shi, Y.X., Tsao, T., Qiu, Y., Kornblau, S.M., Baggerly, K.A., Liu, W., Jessen, K., Liu, Y., Kantarjian, H., Rommel, C., Fruman, D.A., Andreeff, M. & Konopleva, M. (2012) Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment. Blood, 120, 2679-2689.
133. Zent, C.S., LaPlant, B.R., Johnston, P.B., Call, T.G., Habermann, T.M., Micallef, I.N. & Witzig, T.E. (2010) The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer, 9, 2201-2207.
134. Zhang, H., Bajraszewski, N., Wu, E., Wang, H., Moseman, A.P., Dabora, S.L., Griffin, J.D. & Kwiatkowski, D.J. (2007) PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. The Journal of Clinical Investigation, 117, 730-738.