title: Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells.
abstract: OBJECTIVE
  We determined the activity of hsp90 inhibitor, and/or Janus-activated kinase 2 (JAK2) tyrosine kinase inhibitor (TKI), against JAK2-V617F-expressing cultured mouse (Ba/F3-JAK2-V617F) and human (HEL92.1.7 and UKE-1) or primary human CD34(+) myeloproliferative neoplasm (MPN) cells.
  
  
  METHODS
  Following exposure to the hsp90 inhibitor AUY922 and/or JAK2-TKI TG101209, the levels of JAK2-V617F, its downstream signaling proteins, as well as apoptosis were determined.
  
  
  RESULTS
  Treatment with AUY922 induced proteasomal degradation and depletion of JAK2-V617F as well as attenuated the signaling proteins downstream of JAK2-V617F, that is, phospho (p)-STAT5, p-AKT, and p-ERK1/2. AUY922 treatment also induced apoptosis of HEL92.1.7, UKE-1, and Ba/F3-hJAK2-V617F cells. Combined treatment with AUY922 and TG101209 caused greater depletion of the signaling proteins than either agent alone and synergistically induced apoptosis of HEL92.1.7 and UKE-1 cells. Cotreatment with AUY922 and TG101209 also induced significantly more apoptosis of human CD34(+) MPN than normal hematopoietic progenitor cells. As compared with the sensitive controls, JAK2-TKI-resistant HEL/TGR and UKE-1/TGR cells exhibited significantly higher IC(50) values for JAK2-TKI (P < 0.001), which was associated with higher expression of p-JAK2, p-STAT5, p-AKT, and Bcl-xL, but reduced levels of BIM. Unlike the sensitive controls, HEL/TGR and UKE/TGR cells were collaterally sensitive to the hsp90 inhibitors AUY922 and 17-AAG, accompanied by marked reduction in p-JAK2, p-STAT5, p-AKT, and Bcl-xL, with concomitant induction of BIM.
  
  
  CONCLUSIONS
  Findings presented here show that cotreatment with hsp90 inhibitor and JAK2-TKI exerts synergistic activity against cultured and primary MPN cells. In addition, treatment with hsp90 inhibitor may overcome resistance to JAK2-TKI in human MPN cells.
authors: The University of Kansas Cancer Center, Kansas City, USA.
authors: Warren
authors: W
authors: Fiskus
authors: Srdan
authors: S
authors: Verstovsek
authors: Taghi
authors: T
authors: Manshouri
authors: Rekha
authors: R
authors: Rao
authors: Ramesh
authors: R
authors: Balusu
authors: Sreedhar
authors: S
authors: Venkannagari
authors: Nalabothula Narasimha
authors: NN
authors: Rao
authors: Kyungsoo
authors: K
authors: Ha
authors: Jacqueline E
authors: JE
authors: Smith
authors: Stacey L
authors: SL
authors: Hembruff
authors: Sunil
authors: S
authors: Abhyankar
authors: Joseph
authors: J
authors: McGuirk
authors: Kapil N
authors: KN
authors: Bhalla
mesh_terms: D000818:Animals; D018952:Antigens, CD34; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000096:biosynthesis; D000096926:Benzenesulfonamides
chemical_list: D018952:Antigens, CD34; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D012118:Resorcinols; D050799:STAT5 Transcription Factor; D013449:Sulfonamides; D051020:bcl-X Protein; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C522865:TG101209; D000096926:Benzenesulfonamides