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Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms.
J Cell Mol Med 2013; 17(11):1385-96JC

Abstract

Aberrant JAK2 signalling plays a central role in myeloproliferative neoplasms (MPN). JAK2 inhibitors have proven to be clinically efficacious, however, they are not mutation-specific and competent enough to suppress neoplastic clonal haematopoiesis. We hypothesized that, by simultaneously targeting multiple activated signalling pathways, MPN could be more effectively treated. To this end we investigated the efficacy of BEZ235, a dual PI3K/mTOR inhibitor, alone and in combination with the JAK1/JAK2 inhibitor ruxolitinib, in different preclinical models of MPN. Single-agent BEZ235 inhibited the proliferation and induced cell cycle arrest and apoptosis of mouse and human JAK2V617F mutated cell lines at concentrations significantly lower than those required to inhibit the wild-type counterpart, and preferentially prevented colony formation from JAK2V617F knock-in mice and patients' progenitor cells compared with normal ones. Co-treatment of BEZ235 and ruxolitinib produced significant synergism in all these in-vitro models. Co-treatment was also more effective than single drugs in reducing the extent of disease and prolonging survival of immunodeficient mice injected with JAK2V617F-mutated Ba/F3-EPOR cells and in reducing spleen size, decreasing reticulocyte count and improving spleen histopathology in conditional JAK2V617F knock-in mice. In conclusion, combined inhibition of PI3K/mTOR and JAK2 signalling may represent a novel therapeutic strategy in MPN.

Authors+Show Affiliations

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.No 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

24237791

Citation

Bartalucci, Niccolò, et al. "Co-targeting the PI3K/mTOR and JAK2 Signalling Pathways Produces Synergistic Activity Against Myeloproliferative Neoplasms." Journal of Cellular and Molecular Medicine, vol. 17, no. 11, 2013, pp. 1385-96.
Bartalucci N, Tozzi L, Bogani C, et al. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms. J Cell Mol Med. 2013;17(11):1385-96.
Bartalucci, N., Tozzi, L., Bogani, C., Martinelli, S., Rotunno, G., Villeval, J. L., & Vannucchi, A. M. (2013). Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms. Journal of Cellular and Molecular Medicine, 17(11), pp. 1385-96. doi:10.1111/jcmm.12162.
Bartalucci N, et al. Co-targeting the PI3K/mTOR and JAK2 Signalling Pathways Produces Synergistic Activity Against Myeloproliferative Neoplasms. J Cell Mol Med. 2013;17(11):1385-96. PubMed PMID: 24237791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms. AU - Bartalucci,Niccolò, AU - Tozzi,Lorenzo, AU - Bogani,Costanza, AU - Martinelli,Serena, AU - Rotunno,Giada, AU - Villeval,Jean-Luc, AU - Vannucchi,Alessandro M, Y1 - 2013/11/17/ PY - 2013/08/07/received PY - 2013/09/13/accepted PY - 2013/11/19/entrez PY - 2013/11/19/pubmed PY - 2014/7/9/medline KW - BEZ235 KW - JAK2 KW - PI3K pathway KW - in-vivo KW - myeloproliferative disorders SP - 1385 EP - 96 JF - Journal of cellular and molecular medicine JO - J. Cell. Mol. Med. VL - 17 IS - 11 N2 - Aberrant JAK2 signalling plays a central role in myeloproliferative neoplasms (MPN). JAK2 inhibitors have proven to be clinically efficacious, however, they are not mutation-specific and competent enough to suppress neoplastic clonal haematopoiesis. We hypothesized that, by simultaneously targeting multiple activated signalling pathways, MPN could be more effectively treated. To this end we investigated the efficacy of BEZ235, a dual PI3K/mTOR inhibitor, alone and in combination with the JAK1/JAK2 inhibitor ruxolitinib, in different preclinical models of MPN. Single-agent BEZ235 inhibited the proliferation and induced cell cycle arrest and apoptosis of mouse and human JAK2V617F mutated cell lines at concentrations significantly lower than those required to inhibit the wild-type counterpart, and preferentially prevented colony formation from JAK2V617F knock-in mice and patients' progenitor cells compared with normal ones. Co-treatment of BEZ235 and ruxolitinib produced significant synergism in all these in-vitro models. Co-treatment was also more effective than single drugs in reducing the extent of disease and prolonging survival of immunodeficient mice injected with JAK2V617F-mutated Ba/F3-EPOR cells and in reducing spleen size, decreasing reticulocyte count and improving spleen histopathology in conditional JAK2V617F knock-in mice. In conclusion, combined inhibition of PI3K/mTOR and JAK2 signalling may represent a novel therapeutic strategy in MPN. SN - 1582-4934 UR - https://www.unboundmedicine.com/medline/citation/24237791/Co_targeting_the_PI3K/mTOR_and_JAK2_signalling_pathways_produces_synergistic_activity_against_myeloproliferative_neoplasms_ L2 - https://doi.org/10.1111/jcmm.12162 DB - PRIME DP - Unbound Medicine ER -