Progress in Hematology Efficacy and resistance of molecularly targeted therapy for myeloid malignancies

International Journal of Hematology

, Volume 97, Issue 6, pp 695-702

Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms

  • Neha BhagwatAffiliated withHuman Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer CenterGerstner Sloan-Kettering Graduate School in Biomedical Sciences, Memorial Sloan-Kettering Cancer Center
  • , Ross L. LevineAffiliated withHuman Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer CenterGerstner Sloan-Kettering Graduate School in Biomedical Sciences, Memorial Sloan-Kettering Cancer CenterLeukemia Service, Memorial Sloan-Kettering Cancer Center
  • , Priya KoppikarAffiliated withHuman Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center Email author 

Abstract

The discovery of activating mutations in JAK2 and MPL in a majority of patients with myeloproliferative neoplasms (MPN) has led to the rapid clinical development of several JAK kinase inhibitors. Of these, the JAK1/2 inhibitor, ruxolitinib (INCB018424, Incyte Corporation) was recently approved for the treatment of patients with myelofibrosis (MF). JAK inhibitors have effectively reduced splenomegaly and high cytokine levels in patients leading to improvements in quality of life. However, they have not been successful in eliminating the mutant clone in a majority of patients. In vitro studies using saturation mutagenesis screens have revealed several mutations in JAK2 that confer resistance to JAK inhibitors. Nevertheless, these mutations have not been identified so far in JAK inhibitor-treated patients. A recent study from our laboratory demonstrated that chronic JAK kinase inhibition leads to JAK inhibitor persistence via transphosphorylation of JAK2 through other JAK kinase family members. This phenomenon is seen in cell lines, mouse models and patient samples. The JAK inhibitor persistent cells, however, still remain JAK2 dependent and therefore combination therapies that target JAK2 and other components of the JAK–STAT pathway along with JAK inhibitors may provide additional benefits and improve clinical outcomes in these patients.

Keywords

Myeloproliferative neoplasms Tyrosine kinase inhibitors HSP90 inhibitors JAK2 Resistance Persistence Combination therapy