Meyer, Sara C, Keller, Matthew D, Koppikar, Priya, Guryanova, Olga, Rapaport, Franck, Kleppe , Maria, McKenney, Anna-Sophia , Spitzer, Barbara, Mandon, Emeline, Ebel, Nicolas, Andraos-Rey, Rita, Rubert, Joelle, Dammassa, Ernesta, Romanet, Vincent, Doelemeyer, Arno, Zender, Michael, Sellers, William, Hofmann, Francesco, Murakami, Masato, Baffert, Fabienne, Gaul, Christoph, Radimerski, Thomas and Levine, Ross L (2015) NVP-CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms. Cancer Cell.

Abstract

Summary
Although clinically tested JAK inhibitors offer significant benefit to myeloproliferative neoplasm (MPN) patients, they do not induce molecular remissions. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors which bind the active conformation of JAK2 and enable JAK2 transactivation. We investigated if NVP-CHZ868, a novel type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells and in murine MPN models. JAK2/MPL-mutant cell lines were sensitive to NVP-CHZ868, including type I JAK inhibitor-persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition should be pursued as a therapeutic approach for MPN patients.

Significance
Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, they cannot significantly reduce the MPN clone. We previously demonstrated that MPN cells can acquire persistence to type I JAK inhibitors, which bind the active conformation of JAK2 and enable activation of JAK2 in trans by other JAK family members. We show that engaging JAK2 in the inactive conformation with the novel type II inhibitor CHZ868 retains efficacy in type I JAK inhibitor persistent cells, and shows increased efficacy in murine models of polycythemia vera and myelofibrosis, including significant reductions in disease burden not observed with first-generation JAK inhibitors. These data demonstrate that type II JAK inhibitors improve the targeting of aberrant JAK2 signaling, offering increased therapeutic efficacy.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/23848