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

Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Rekha Rao, Ramesh Balusu, Sreedhar Venkannagari, Narasimha Rao Nalabothula, Kyungsoo Ha, Jacqueline E. Smith, Stacey L. Hembruff, Sunil Abhyankar, Joseph McGuirk, Kapil N. Bhalla

Research output: Contribution to journalArticle

70 Scopus citations

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 primaryMPNcells. In addition, treatment with hsp90 inhibitor may overcome resistance to JAK2-TKI in human MPN cells.

Original languageEnglish (US)
Pages (from-to)7347-7358
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number23
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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