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Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells.
Mol Cancer Ther 2013; 12(5):577-88MC

Abstract

Hemopoietic progenitor cells (HPC) from myeloproliferative neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs.

Authors+Show Affiliations

The University of Kansas Cancer Center, Kansas City, KS, USA.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

Language

eng

PubMed ID

23445613

Citation

Fiskus, Warren, et al. "Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor Against Cultured and Primary Human Myeloproliferative Neoplasm Cells." Molecular Cancer Therapeutics, vol. 12, no. 5, 2013, pp. 577-88.
Fiskus W, Verstovsek S, Manshouri T, et al. Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol Cancer Ther. 2013;12(5):577-88.
Fiskus, W., Verstovsek, S., Manshouri, T., Smith, J. E., Peth, K., Abhyankar, S., ... Bhalla, K. N. (2013). Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Molecular Cancer Therapeutics, 12(5), pp. 577-88. doi:10.1158/1535-7163.MCT-12-0862.
Fiskus W, et al. Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor Against Cultured and Primary Human Myeloproliferative Neoplasm Cells. Mol Cancer Ther. 2013;12(5):577-88. PubMed PMID: 23445613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. AU - Fiskus,Warren, AU - Verstovsek,Srdan, AU - Manshouri,Taghi, AU - Smith,Jacqueline E, AU - Peth,Karissa, AU - Abhyankar,Sunil, AU - McGuirk,Joseph, AU - Bhalla,Kapil N, Y1 - 2013/02/27/ PY - 2013/3/1/entrez PY - 2013/3/1/pubmed PY - 2013/12/16/medline SP - 577 EP - 88 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 12 IS - 5 N2 - Hemopoietic progenitor cells (HPC) from myeloproliferative neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/23445613/Dual_PI3K/AKT/mTOR_inhibitor_BEZ235_synergistically_enhances_the_activity_of_JAK2_inhibitor_against_cultured_and_primary_human_myeloproliferative_neoplasm_cells_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23445613 DB - PRIME DP - Unbound Medicine ER -