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mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.
PLoS One 2013; 8(1):e54826Plos

Abstract

BACKGROUND

Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells.

FINDINGS

Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001) and an ATP-competitive (PP242) mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib). mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with polycythemia vera.

CONCLUSIONS/SIGNIFICANCE

These findings support mTOR inhibitors as novel potential drugs for the treatment of MPN and advocate for clinical trials exploiting the combination of mTOR and JAK2 inhibitor.

Authors+Show Affiliations

Department of Medical and Surgical Care, Section of Hematology, University of Florence, Florence, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23382981

Citation

Bogani, Costanza, et al. "MTOR Inhibitors Alone and in Combination With JAK2 Inhibitors Effectively Inhibit Cells of Myeloproliferative Neoplasms." PloS One, vol. 8, no. 1, 2013, pp. e54826.
Bogani C, Bartalucci N, Martinelli S, et al. MTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS ONE. 2013;8(1):e54826.
Bogani, C., Bartalucci, N., Martinelli, S., Tozzi, L., Guglielmelli, P., Bosi, A., & Vannucchi, A. M. (2013). MTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PloS One, 8(1), pp. e54826. doi:10.1371/journal.pone.0054826.
Bogani C, et al. MTOR Inhibitors Alone and in Combination With JAK2 Inhibitors Effectively Inhibit Cells of Myeloproliferative Neoplasms. PLoS ONE. 2013;8(1):e54826. PubMed PMID: 23382981.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. AU - Bogani,Costanza, AU - Bartalucci,Niccolò, AU - Martinelli,Serena, AU - Tozzi,Lorenzo, AU - Guglielmelli,Paola, AU - Bosi,Alberto, AU - Vannucchi,Alessandro M, AU - ,, Y1 - 2013/01/31/ PY - 2012/07/23/received PY - 2012/12/17/accepted PY - 2013/2/6/entrez PY - 2013/2/6/pubmed PY - 2013/8/2/medline SP - e54826 EP - e54826 JF - PloS one JO - PLoS ONE VL - 8 IS - 1 N2 - BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001) and an ATP-competitive (PP242) mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib). mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with polycythemia vera. CONCLUSIONS/SIGNIFICANCE: These findings support mTOR inhibitors as novel potential drugs for the treatment of MPN and advocate for clinical trials exploiting the combination of mTOR and JAK2 inhibitor. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23382981/mTOR_inhibitors_alone_and_in_combination_with_JAK2_inhibitors_effectively_inhibit_cells_of_myeloproliferative_neoplasms_ L2 - http://dx.plos.org/10.1371/journal.pone.0054826 DB - PRIME DP - Unbound Medicine ER -