Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/ CIP2A axis
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Niccolò Bartalucci1,2,3, Laura Calabresi1,2,3, Manjola Balliu1,2,3, Serena Martinelli1,2,3, Maria Caterina Rossi2,3, Jean Luc Villeval4, Francesco Annunziato2,3, Paola Guglielmelli1,2,3 and Alessandro M. Vannucchi1,2,3
1CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
2Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
3DENOTHE Excellence Center, Florence, Italy
4INSERM, Unité Mixte de Recherche (UMR) 1170, Institut Gustave Roussy, Villejuif, France
Alessandro M. Vannucchi, email: [email protected]
Keywords: STAT5, phosphorylation, MPN, ruxolitinib, PI3K/mTOR inhibitors
Received: February 28, 2017 Accepted: May 10, 2017 Published: May 22, 2017
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.
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