Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Rekha Rao, Ramesh Balusu, Sreedhar Venkannagari, Nalabothula Narasimha Rao, Kyungsoo Ha, Jacqueline E Smith, Stacey L Hembruff, Sunil Abhyankar, Joseph McGuirk, Kapil N Bhalla
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 23 Pg. 7347-58 (Dec 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21976548 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2011 AACR.

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antigens, CD34
• HSP90 Heat-Shock Proteins
• Isoxazoles
• Pyrimidines
• Resorcinols
• STAT5 Transcription Factor
• Sulfonamides
• TG101209
• bcl-X Protein
• Janus Kinase 2
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antigens, CD34
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Drug Resistance, Neoplasm
• Drug Synergism
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Hematopoietic Stem Cells (drug effects)
• Humans
• Isoxazoles (pharmacology)
• Janus Kinase 2 (antagonists & inhibitors, biosynthesis, metabolism)
• Mice
• Myeloproliferative Disorders (drug therapy, metabolism)
• Proto-Oncogene Proteins c-akt (biosynthesis)
• Pyrimidines (pharmacology)
• Resorcinols (pharmacology)
• STAT5 Transcription Factor (biosynthesis)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured
• bcl-X Protein (biosynthesis)