Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells Journal Article
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| Authors: | Fiskus, Warren; Verstovsek, Srdan; Manshouri Taghi; Smith Jacqueline E; Peth, Karissa; Abhyankar, Sunil; McGuirk, Joseph; Bhalla, Kapil N |
| Article Title: | Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells |
| Alternate Title: | Molecular cancer therapeutics |
| Journal Title: | Mol. Cancer Ther. |
| ISSN: | 1538-8514 |
| Publisher: | Unknown |
| Date Published: | 2013 |
| DOI/URL: | |
| Notes: | Hemopoietic progenitor cells (HPCs) from myeloproliferative neoplasms (MPNs) such as myelofibrosis (MF) 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), e.g., 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 MF or significantly improve survival of patients with advanced MF. Here, we demonstrate that treatment with the dual 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+ 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. Co-treatment 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 MF HPCs. |
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