Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms

被引:0
作者
Neha Bhagwat
Ross L. Levine
Priya Koppikar
机构
[1] Memorial Sloan-Kettering Cancer Center,Human Oncology and Pathogenesis Program
[2] Gerstner Sloan-Kettering Graduate School in Biomedical Sciences,Leukemia Service
[3] Memorial Sloan-Kettering Cancer Center,undefined
[4] Memorial Sloan-Kettering Cancer Center,undefined
来源
International Journal of Hematology | 2013年 / 97卷
关键词
Myeloproliferative neoplasms; Tyrosine kinase inhibitors; HSP90 inhibitors; JAK2; Resistance; Persistence; Combination therapy;
D O I
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中图分类号
学科分类号
摘要
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.
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页码:695 / 702
页数:7
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