JAK2 inhibitors in the treatment of myeloproliferative neoplasms

Raoul Tibes, James M. Bogenberger, Holly L. Geyer, Ruben A. Mesa

Research output: Contribution to journalReview article

15 Scopus citations

Abstract

Introduction: Dysregulation of JAK-STAT signaling is a pathogenetic hallmark of myeloproliferative neoplasms (MPNs) arising from several distinct molecular aberrations, including mutations in JAK2, the thrombopoietin receptor (MPL), mutations in negative regulators of JAK-STAT signaling, such as lymphocyte-specific adapter protein (SH2B3), and epigenetic dysregulation as seen with Suppressor of Cytokine Signaling (SOCS) proteins. In addition, growth factor/cytokine stimulatory events activate JAK-STAT signaling independent of mutations. Areas covered: The various mutations and molecular events activating JAK-STAT signaling in MPNs are reviewed. Detailed inhibitory kinase profiles of the currently developed JAK inhibitors are presented. Clinical trial results for currently developed JAK targeting agents are comprehensively summarized. The limitations of JAK-STAT targeting in MPNs, as well as potential rational combination therapies with JAK2 inhibitors, are discussed. Expert opinion: Aberrant JAK-STAT signaling is an underlying theme in the pathogenesis of MPNs. While JAK2 inhibitors are active in JAK2V617F and wild-type JAK2 MPNs, JAK2V617F mutation-specific or JAK2-selective inhibitors may possess unique clinical attributes. Complimentary targeting of parallel pathways operating in MPNs may offer novel therapeutic approaches in combination with JAK inhibition. Understanding the intricacies of JAK-STAT pathway activation, including growth factor/cytokine-driven signaling, will open new avenues for therapeutic intervention at known and novel molecular vulnerabilities of MPNs.

Original languageEnglish (US)
Pages (from-to)1755-1774
Number of pages20
JournalExpert Opinion on Investigational Drugs
Volume21
Issue number12
DOIs
Publication statusPublished - Dec 1 2012

    Fingerprint

Keywords

  • Acute leukemia
  • Essential thrombocythemia
  • JAK-STAT pathway
  • JAK2 inhibitors
  • Myeloproliferative neoplasms
  • Polycythemia vera, myelofibrosis
  • Primary myelofibrosis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this