Top

Published in:

01-03-2011 | Review

Mammalian target of rapamycin as a target in hematological malignancies

Authors: Kevin R. Kelly, Julie H. Rowe, Swaminathan Padmanabhan, Steffan T. Nawrocki, Jennifer S. Carew

Published in: Targeted Oncology | Issue 1/2011

Abstract

The mammalian target of rapamycin (mTOR) regulates protein synthesis in addition to cell growth and cell proliferation. Elucidation of the roles of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway in the regulation of the pathogenesis of hematological neoplasms has led to the development and clinical evaluation of agents targeting this pathway for the treatment of leukemia and lymphomas. Clinical trials conducted to date have shown modest responses to mTOR inhibition in patients with various hematological malignancies. Novel agents that simultaneously target mTOR complex 2 (mTORC2) or AKT in addition to mTOR complex 1 (mTORC1) may offer an opportunity to improve therapeutic efficacy.

Brown EJ et al (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369(6483):756–758PubMedCrossRef

Hardwick JS et al (1999) Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci USA 96(26):14866–14870PubMedCrossRef

Powers T, Walter P (1999) Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol Biol Cell 10(4):987–1000PubMed

Jacinto E, Hall MN (2003) Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 4(2):117–126PubMedCrossRef

Hentges KE et al (2001) FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proc Natl Acad Sci USA 98(24):13796–13801PubMedCrossRef

WullschlegerS LR, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484CrossRef

Hara K et al (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110(2):177–189PubMedCrossRef

Bjornsti MA, Houghton P (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4(5):335–348PubMedCrossRef

Hay N, Onenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945PubMedCrossRef

10.

Pullen N, Thomas G (1997) The modular phosphorylation and activation of p70s6k. FEBS Lett 410(1):78–82PubMedCrossRef

11.

Pause A et al (1994) Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 371(6500):762–767PubMedCrossRef

12.

Frias MA et al (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16(18):1865–1870PubMedCrossRef

13.

Sarbassov DD et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302PubMedCrossRef

14.

Sarbassov DD et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168PubMedCrossRef

15.

Pullen N et al (1998) Phosphorylation and activation of p70s6k by PDK1. Science 279(5351):707–710PubMedCrossRef

16.

Sarbassov DD et al (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101PubMedCrossRef

17.

Long X et al (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15(8):702–713PubMedCrossRef

18.

Chapuis N et al (2010) Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies. Leukemia 24(10):1686–1699PubMedCrossRef

19.

Nicklin P et al (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521–534PubMedCrossRef

20.

Inoki K et al (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126(5):955–968PubMedCrossRef

21.

Shayesteh L et al (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21(1):99–102PubMedCrossRef

22.

Mirza AM et al (2000) Oncogenic transformation of cells by a conditionally active form of the protein kinase Akt/PKB. Cell Growth Differ 11(6):279–292PubMed

23.

Chu EC, Tarnawski AS (2004) PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit 10(10):RA235–241PubMed

24.

Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501PubMedCrossRef

25.

Chen W et al (2010) mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. Mol Cancer 9:292PubMedCrossRef

26.

Kharas MG et al (2004) Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood 103(11):4268–4275PubMedCrossRef

27.

Hu L et al (2003) Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 101(8):3126–3135PubMedCrossRef

28.

Hyun T et al (2000) Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood 96(10):3560–3568PubMed

29.

Siekierka JJ et al (1989) A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341(6244):755–757PubMedCrossRef

30.

Eng CP, Sehgal SN, Vezina C (1984) Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37(10):1231–1237

31.

Hidalgo M et al (2006) A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12(19):5755–5763PubMedCrossRef

32.

Schuler W et al (1997) SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 64(1):36–42PubMedCrossRef

33.

O’Donnell A et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26(10):1588–1595PubMedCrossRef

34.

Mahalingam D et al (2009) Targeting the mTOR pathway using deforolimus in cancer therapy. Future Oncol 5(3):291–303PubMedCrossRef

35.

Mita MM et al (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26(3):361–367PubMedCrossRef

36.

Vilar E, Perez-Garcia J, Tabernero J (2011) Pushing the envelope in the mTOR pathway. The second generation of inhibitors. Mol Cancer Ther. doi:10.1158/1535-7163.MCT-10-0905 PubMed

37.

Feldman ME et al (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38PubMedCrossRef

38.

Garcia-Martinez JM et al (2009) Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J421(1):29–42CrossRef

39.

Thoreen CC et al (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023–8032PubMedCrossRef

40.

Yu K et al (2009) Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69(15):6232–6240PubMedCrossRef

41.

Chresta CM et al (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 Res 70(1):288–298PubMedCrossRef

42.

Chapuis N et al (2010) Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin Cancer Res 16(22):5424–5435PubMedCrossRef

43.

Cho DC et al (2010) The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma. Clin Cancer Res 16(14):3628–3638PubMedCrossRef

44.

Care RS et al (2003) Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol 121(5):775–777PubMedCrossRef

45.

Recher C et al (2005) mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle 4(11):1540–1549PubMedCrossRef

46.

Xu Q et al (2003) Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102(3):972–980PubMedCrossRef

47.

Xu Q, Thompson JE, Carroll M (2005) mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood 106(13):4261–4268PubMedCrossRef

48.

Chen W et al (2010) mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. Mol Cancer 9:292PubMedCrossRef

49.

Recher C et al (2005) Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 105(6):2527–2534PubMedCrossRef

50.

Zeng Z et al (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109(8):3509–3512PubMedCrossRef

51.

Perl AE et al (2009) A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res 15(21):6732–6739PubMedCrossRef

52.

Guzman ML et al (2001) Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98(8):2301–2307PubMedCrossRef

53.

Nyakern M et al (2006) Frequent elevation of Akt kinase phosphorylation in blood marrow and peripheral blood mononuclear cells from high-risk myelodysplastic syndrome patients. Leukemia 20(2):230–238PubMedCrossRef

54.

Follo MY et al (2007) The Akt/mammalian target of rapamycin signal transduction pathway is activated in high-risk myelodysplastic syndromes and influences cell survival and proliferation. Cancer Res 67(9):4287–4294PubMedCrossRef

55.

Yee KW et al (2006) Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 12(17):5165–5173PubMedCrossRef

56.

Younes H et al (2007) Targeting the phosphatidylinositol 3-kinase pathway in multiple myeloma. Clin Cancer Res 13(13):3771–3775PubMedCrossRef

57.

Hsu J et al (2001) The AKT kinase is activated in multiple myeloma tumor cells. Blood 98(9):2853–2855PubMedCrossRef

58.

Frost P et al (2004) In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 104(13):4181–4187PubMedCrossRef

59.

Stromberg T et al (2004) Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103(8):3138–3147PubMedCrossRef

60.

Wan X et al (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940PubMedCrossRef

61.

Hoang B et al (2010) Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 116(22):4560–4568PubMedCrossRef

62.

Kelly KR et al (2010) The novel Aurora A kinase inhibitor MLN8237 is active in resistant chronic myeloid leukemia and significantly increases the efficacy of nilotinib. J Cell Mol Med. doi:10.1111/j.1582-4934.2010.01218.x

63.

Mayerhofer M et al (2002) BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 100(10):3767–3775PubMedCrossRef

64.

Ly C et al (2003) Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 63(18):5716–5722PubMed

65.

Kim JH et al (2005) Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species. Blood 105(4):1717–1723PubMedCrossRef

66.

Carayol N et al (2008) Suppression of programmed cell death 4 (PDCD4) protein expression by BCR-ABL-regulated engagement of the mTOR/p70 S6 kinase pathway. J Biol Chem 283(13):8601–8610PubMedCrossRef

67.

Burchert A et al (2005) Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19(10):1774–1782PubMedCrossRef

68.

Mohi MG et al (2004) Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 101(9):3130–3135PubMedCrossRef

69.

Mancini M et al (2010) mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. Leuk Res 34(5):641–648PubMedCrossRef

70.

Carayol N et al (2010) Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci USA 107(28):12469–12474PubMedCrossRef

71.

Ringshausen I, Peschel DT (2005) Mammalian target of rapamycin (mTOR) inhibition in chronic lymphocytic B-cell leukemia: a new therapeutic option. Leuk Lymphoma 46(1):11–19PubMedCrossRef

72.

Decker T et al (2003) Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood 101(1):278–285PubMedCrossRef

73.

Zanesi N et al (2006) Effect of rapamycin on mouse chronic lymphocytic leukemia and the development of nonhematopoietic malignancies in Emu-TCL1 transgenic mice. Cancer Res 66(2):915–920PubMedCrossRef

74.

Decker T et al (2009) A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL. Ann Hematol 88(3):221–227PubMedCrossRef

75.

Zent CS et al (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 116(9):2201–2207PubMed

76.

Ansell SM et al (2008) Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer 113(3):508–514PubMedCrossRef

77.

Witzig TE et al (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23(23):5347–5356PubMedCrossRef

78.

Hess G et al (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27(23):3822–3829PubMedCrossRef

79.

Leseux L et al (2006) Syk-dependent mTOR activation in follicular lymphoma cells. Blood 108(13):4156–4162PubMedCrossRef

80.

Ruggero D et al (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10(5):484–486PubMedCrossRef

81.

Wanner K et al (2006) Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol 134(5):475–484PubMedCrossRef

82.

Smith SM et al (2010) Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol 28(31):4740–4746PubMedCrossRef

83.

Armand P et al (2008) Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol 26(35):5767–5774PubMedCrossRef

84.

Witzig TE et al (2011) A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 25(2):341–347PubMedCrossRef

85.

Johnston PB et al (2010) A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol 85(5):320–324PubMed

86.

87.

Smith SM et al (2010) Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol 28(31):4740–4746PubMedCrossRef

88.

Rizzieri DA et al (2008) A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 14(9):2756–2762PubMedCrossRef

Title: Mammalian target of rapamycin as a target in hematological malignancies
Authors: Kevin R. Kelly
Julie H. Rowe
Swaminathan Padmanabhan
Steffan T. Nawrocki
Jennifer S. Carew
Publication date: 01-03-2011
Publisher: Springer-Verlag
Published in: Targeted Oncology / Issue 1/2011
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-011-0175-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2011

The emerging role of mammalian target of rapamycin inhibitors in the treatment of sarcomas

Aging and cancer: can mTOR inhibitors kill two birds with one drug?

Future directions of mammalian target of rapamycin (mTOR) inhibitor therapy in renal cell carcinoma

Targeting the target of rapamycin (TOR): looking to mother nature

Mechanisms of mTOR inhibitor resistance in cancer therapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer