Title:JAK Inhibitors: Pharmacology and Clinical Activity in Chronic Myeloprolipherative Neoplasms
Volume: 20
Issue: 9
Author(s): J. Trelinski and T. Robak
Affiliation:
Keywords:
Pan-JAK inhibitors, JAK2-specific inhibitors, JAK3-specific inhibitor, tofacitinib, Janus family kinases (JAKs), cell growth, non-receptor protein, tyrosine kinases, polycythemia vera (PV), myeloproliferative
Abstract: The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development,
and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. They form a subgroup
of the non-receptor protein tyrosine kinases. Activating mutations within each of the JAKs is associated with malignant
transformations; the most common are mutations of JAK2 in polycythemia vera (PV) and other myeloproliferative neoplasms
(MPN). Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough
in the understanding of MPN disease pathogenesis. The JAK2 V617F mutation is present in the majority of PV patients,
and about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) are affected. This mutation
leads to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling
networks. JAK2 ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the
treatment of MPN. JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with
minimal toxicity. These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other
MPN. However, some of these inhibitors have additional unique effects. Ruxolitinib causes a significant reduction in the
level of pro-inflammatory cytokines. Another inhibitor, CYT387, improves anemia. Many other JAK2 inhibitors such as
TG101348 or SAR302503, SB1518, CEP701 and LY2784544 are now under investigation for MPN development. In contrast
tasocitinib, a predominantly JAK3 inhibitor, is being evaluated in a number of inflammatory and immunological diseases,
including rheumatoid arthritis, psoriasis, ulcerative colitis, dry eye disease and in kidney transplant patients. In conclusion
the use of JAK inhibitors in MPN and some of the immune-mediated disorders is a promising new strategy for
therapy. However, definitive data from ongoing and future preclinical and clinical trials will aid in better defining the
status of these drugs in the treatment of these diseases.
