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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

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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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CoChat. (2026). Citation check: Rationale for Targeting the PI3K/Akt/mTOR Pathway in Myeloproliferative Neoplasms. https://app.cochat.ai/papers/10.1016/j.clml.2013.07.011
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Bartalucci, N., Guglielmelli, P., & Vannucchi, A. M. (2013). Rationale for Targeting the PI3K/Akt/mTOR Pathway in Myeloproliferative Neoplasms. Clinical Lymphoma Myeloma and Leukemia. https://doi.org/10.1016/j.clml.2013.07.011