mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms
| Autor: | Costanza Bogani, Niccolò Bartalucci, Serena Martinelli, Lorenzo Tozzi, Paola Guglielmelli, Alberto Bosi, Alessandro M Vannucchi, Associazione Italiana per la Ricerca sul Cancro AGIMM Gruppo Italiano Malattie Mieloproliferative |
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| Rok vydání: | 2012 |
| Předmět: |
Ruxolitinib
Indoles lcsh:Medicine Antigens CD34 Pharmacology Signal transduction Hematologic Cancers and Related Disorders Mice Molecular cell biology Bone Marrow jak2 inhibitor Bone and Soft Tissue Sarcomas lcsh:Science Multidisciplinary TOR Serine-Threonine Kinases JAK-STAT signaling pathway food and beverages Drug Synergism Tor signaling Hematology Oncology Medicine Cellular Types Cell Division medicine.drug Research Article Immunology Signaling in cellular processes PIM1 Bone Marrow Cells Biology Cell Line Colony-Forming Units Assay Inhibitory Concentration 50 Myeloproliferative Disorders medicine Animals Humans Everolimus Progenitor cell Myelofibrosis Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation Sirolimus STAT signaling family lcsh:R Cancers and Neoplasms Janus Kinase 2 medicine.disease Hematopoietic Stem Cells Pyrimidines Purines Case-Control Studies Immune System Mutation Pyrazoles lcsh:Q Clinical Immunology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 1, p e54826 (2013) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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