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Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722516/ https://www.ncbi.nlm.nih.gov/pubmed/29228564 http://dx.doi.org/10.18632/oncotarget.18073 |
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author | Bartalucci, Niccolò Calabresi, Laura Balliu, Manjola Martinelli, Serena Rossi, Maria Caterina Villeval, Jean Luc Annunziato, Francesco Guglielmelli, Paola Vannucchi, Alessandro M. |
author_facet | Bartalucci, Niccolò Calabresi, Laura Balliu, Manjola Martinelli, Serena Rossi, Maria Caterina Villeval, Jean Luc Annunziato, Francesco Guglielmelli, Paola Vannucchi, Alessandro M. |
author_sort | Bartalucci, Niccolò |
collection | PubMed |
description | Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors. We found that PI3K/mTOR-dependent phosphorylation of STAT5b serine residues involves Protein Phosphatase 2A and its repressor CIP2A. The levels of CIP2A were found increased in cells harboring the JAK2V617F mutation, and we provide evidence of a correlation between clinical responses and the extent of CIP2A downregulation in myelofibrosis patients receiving the mTOR inhibitor RAD001 in a phase II clinical trial. To achieve maximal inhibition of STAT5 phosphorylation, we combined ruxolitinib with BKM120, a PI3K inhibitor, and RAD001, an mTOR inhibitor, obtaining improved efficacy in JAK2V617F mutated cell lines, primary patients’ cells, and JAK2V617F knock-in mice. These findings contribute to understanding the effectiveness of PI3K/mTOR inhibitors in MPN and argue for the rationale to develop combination clinical trials. |
format | Online Article Text |
id | pubmed-5722516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57225162017-12-10 Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis Bartalucci, Niccolò Calabresi, Laura Balliu, Manjola Martinelli, Serena Rossi, Maria Caterina Villeval, Jean Luc Annunziato, Francesco Guglielmelli, Paola Vannucchi, Alessandro M. Oncotarget Research Paper Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors. We found that PI3K/mTOR-dependent phosphorylation of STAT5b serine residues involves Protein Phosphatase 2A and its repressor CIP2A. The levels of CIP2A were found increased in cells harboring the JAK2V617F mutation, and we provide evidence of a correlation between clinical responses and the extent of CIP2A downregulation in myelofibrosis patients receiving the mTOR inhibitor RAD001 in a phase II clinical trial. To achieve maximal inhibition of STAT5 phosphorylation, we combined ruxolitinib with BKM120, a PI3K inhibitor, and RAD001, an mTOR inhibitor, obtaining improved efficacy in JAK2V617F mutated cell lines, primary patients’ cells, and JAK2V617F knock-in mice. These findings contribute to understanding the effectiveness of PI3K/mTOR inhibitors in MPN and argue for the rationale to develop combination clinical trials. Impact Journals LLC 2017-05-22 /pmc/articles/PMC5722516/ /pubmed/29228564 http://dx.doi.org/10.18632/oncotarget.18073 Text en Copyright: © 2017 Bartalucci et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Bartalucci, Niccolò Calabresi, Laura Balliu, Manjola Martinelli, Serena Rossi, Maria Caterina Villeval, Jean Luc Annunziato, Francesco Guglielmelli, Paola Vannucchi, Alessandro M. Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis |
title | Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis |
title_full | Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis |
title_fullStr | Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis |
title_full_unstemmed | Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis |
title_short | Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis |
title_sort | inhibitors of the pi3k/mtor pathway prevent stat5 phosphorylation in jak2v617f mutated cells through pp2a/cip2a axis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722516/ https://www.ncbi.nlm.nih.gov/pubmed/29228564 http://dx.doi.org/10.18632/oncotarget.18073 |
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