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Rationale for Targeting the PI3K/Akt/mTOR Pathway in Myeloproliferative Neoplasms

Bartalucci, Niccolò, Guglielmelli, Paola, Vannucchi, Alessandro M.·2013·Clinical Lymphoma Myeloma and Leukemia
DOI 10.1016/j.clml.2013.07.011
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Abstract

The chronic myeloproliferative neoplasms (MPNs), are characterized by a Janus Kinase (JAK)-2 V617F point mutation but this molecular abnormality does not explain by itself the pathogenesis of these disorders, or the phenotypic diversity associated with essential thrombocythemia, polycythemia vera (PV), and myelofibrosis. Beyond the JAK/signal transducer and activator of transcription network, a wide number of molecular alterations were described in MPN including the fosfatidilinositolo-3-chinasi (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway constitutive activation. Several pathway inhibitors were developed, including everolimus, up to the latest class of catalytic inhibitors such as BKM120 and BEZ235. In this review, we present some clinical and experimental evidence showing that the PI3K/Akt/mTOR pathway could represent a therapeutic target in MPNs. In in vitro studies, everolimus has been shown to inhibit cell proliferation and clonogenic potential in human and murine JAK2 V617F mutated cell lines. Patients with PV and primary myelofibrosis hematopoietic progenitors were significantly more sensitive to everolimus compared with healthy control subjects. Of much interest, a combination of everolimus and the JAK1/2 inhibitor, ruxolitinib, showed strong synergism in inducing cell cycle arrest and blockade of cell proliferation. Similar data were obtained using a dual PI3K/mTOR inhibitor, BEZ235, with activity that was also shown in preclinical murin…

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Research works printed but not linked: 24

  1. Prchal, 1974, Bone-marrow responses in polycythemia vera, N Engl J Med, 290, 1382, 10.1056/NEJM197406132902419 · DOI
  2. Dupont, 2007, The JAK2 V617F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera, Blood, 110, 1013, 10.1182/blood-2006-10-054940 · DOI
  3. Li, 2010, JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia, Blood, 116, 1528, 10.1182/blood-2009-12-259747 · DOI
  4. Akada, 2010, Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease, Blood, 115, 3589, 10.1182/blood-2009-04-215848 · DOI
  5. Ugo, 2004, Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera, Exp Hematol, 32, 179, 10.1016/j.exphem.2003.11.003 · DOI
  6. Foster, 2012, Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies, Pharmacol Rev, 64, 1027, 10.1124/pr.110.004051 · DOI
  7. Feng, 2005, The coordinate regulation of the p53 and mTOR pathways in cells, Proc Natl Acad Sci U S A, 102, 8204, 10.1073/pnas.0502857102 · DOI · Paper page
  8. Dowling, 2010, mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs, Science, 328, 1172, 10.1126/science.1187532 · DOI
  9. Hsieh, 2010, Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E, Cancer Cell, 17, 249, 10.1016/j.ccr.2010.01.021 · DOI · Paper page
  10. McCubrey, 2012, Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades, Oncotarget, 3, 954, 10.18632/oncotarget.652 · DOI
  11. Hietakangas, 2008, TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells, BMC Cancer, 8, 282, 10.1186/1471-2407-8-282 · DOI
  12. Guertin, 2009, mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice, Cancer Cell, 15, 148, 10.1016/j.ccr.2008.12.017 · DOI · Paper page
  13. Lluis, 2009, Somatic cell reprogramming control: signaling pathway modulation versus transcription factor activities, Cell Cycle, 8, 1138, 10.4161/cc.8.8.8206 · DOI
  14. Wu, 2000, 17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes, Cancer Res, 60, 5371
  15. Lenz, 2010, Aggressive lymphomas, N Engl J Med, 362, 1417, 10.1056/NEJMra0807082 · DOI
  16. Peterson, 2009, DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival, Cell, 137, 873, 10.1016/j.cell.2009.03.046 · DOI · Paper page
  17. Brandts, 2005, Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation, Cancer Res, 65, 9643, 10.1158/0008-5472.CAN-05-0422 · DOI · Paper page
  18. Kharas, 2005, ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors, Cancer Res, 65, 2047, 10.1158/0008-5472.CAN-04-3888 · DOI
  19. Grimwade, 2009, Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms, Br J Haematol, 147, 495, 10.1111/j.1365-2141.2009.07870.x · DOI · Paper page
  20. Vicari, 2012, Increased phospho-mTOR expression in megakaryocytic cells derived from CD34+ progenitors of essential thrombocythaemia and myelofibrosis patients, Br J Haematol, 159, 237, 10.1111/j.1365-2141.2012.09246.x · DOI
  21. James, 2005, A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera, Nature, 434, 1144, 10.1038/nature03546 · DOI
  22. Bogani, 2013, mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms, PlosOne, 8(1), e54826, 10.1371/journal.pone.0054826 · DOI
  23. Vannucchi, 2011, Inhibitors of PI3K/Akt and/or mTOR Inhibit the Growth of Cells of Myeloproliferative Neoplasms and Synergize with JAK2 Inhibitor and Interferon. ASH International Conference, Blood, 118, 1638, 10.1182/blood.V118.21.3835.3835 · DOI
  24. Guglielmelli, 2011, Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis, Blood, 118, 2069, 10.1182/blood-2011-01-330563 · DOI

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Metadata

Authors
Bartalucci, N., Guglielmelli, P., & Vannucchi, A. M.
Venue
Clinical Lymphoma Myeloma and Leukemia
Publisher
Elsevier BV
Published
2013-09
Volume
13
Pages
S307-S309
ISSN
2152-2650
DOI
10.1016/j.clml.2013.07.011
Cited by
49
References
0
Language
en
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