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Combined Inhibition of Janus Kinase 1/2 for the Treatment of JAK2V617F-Driven Neoplasms: Selective Effects on Mutant Cells and Improvements in Measures of Disease Severity
Ist Teil von
Clinical cancer research, 2009-11, Vol.15 (22), p.6891-6900
Ort / Verlag
United States: American Association for Cancer Research
Erscheinungsjahr
2009
Quelle
Electronic Journals Library
Beschreibungen/Notizen
Purpose: Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for
the Philadelphia chromosome–negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary
myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy.
Experimental Design: A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell
lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient
cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight,
and disease-associated inflammatory markers were measured.
Results: INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F
mutation by blocking JAK-STAT signaling and inducing apoptosis. In vivo , INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight
gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly
elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon
treatment.
Conclusions: These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen
size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of
JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients
with myeloproliferative diseases and other neoplasms associated with JAK dysregulation. (Clin Cancer Res 2009;15(22):6891–900)