title: Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells.
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: The University of Kansas Cancer Center, Kansas City, KS, USA.
authors: Warren
authors: W
authors: Fiskus
authors: Srdan
authors: S
authors: Verstovsek
authors: Taghi
authors: T
authors: Manshouri
authors: Jacqueline E
authors: JE
authors: Smith
authors: Karissa
authors: K
authors: Peth
authors: Sunil
authors: S
authors: Abhyankar
authors: Joseph
authors: J
authors: McGuirk
authors: Kapil N
authors: KN
authors: Bhalla
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D007093:Imidazoles; D053614:Janus Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011759:Pyrrolidines; D011804:Quinolines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C528327:fedratinib; D000096926:Benzenesulfonamides; C531198:dactolisib