Pairing JAK with MEK for improved therapeutic efficiency in myeloproliferative disorders
David A. Williams
David A. Williams
Published April 1, 2019; First published March 4, 2019
Citation Information: J Clin Invest. 2019;129(4):1519-1521. https://doi.org/10.1172/JCI127582.
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Commentary

Pairing JAK with MEK for improved therapeutic efficiency in myeloproliferative disorders

Abstract

The identification of JAK2 mutations as disease-initiating in myeloproliferative neoplasms (MPNs) has led to new and effective therapies for these diseases. In a study published in this issue of the JCI, Stivala et al. explored the key observation that JAK inhibition successfully suppresses MAPK activation in MPN cell lines and primary MPN cells in vitro, and the finding that it failed to completely and effectively suppress MAPK activation in vivo in two mouse models. The authors went on to show that dual inhibition of JAK and the MAP kinase pathway provided enhanced therapeutic efficacy in the in vivo models of MPN.

Authors

David A. Williams

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Figure 1

Inhibiting the JAK pathway in MPN.

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Inhibiting the JAK pathway in MPN. (A and B) Ex vivo inhibition strategy...
(A and B) Ex vivo inhibition strategy. Activation of the JAK pathway leads to enhanced cell proliferation, a hallmark of MPN. JAK2 inhibition ex vivo inhibits MEK/ERK signaling, ultimately leading to a reduction in cell proliferation. (C and D) In vivo inhibition strategy. JAK2 inhibitors are not able to induce molecular remissions in vivo. JAK2-independent compensatory activation of the MEK/ERK signaling pathway is attributed to activated PDGFR. Combined targeting of JAK2 and MEK inhibits ERK activation and reduces cell proliferation in vivo. MPLR, thrombopoietin receptor. Figure illustrated by Rachel Davidowitz.