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CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

2015; Cell Press; Volume: 28; Issue: 1 Linguagem: Inglês

10.1016/j.ccell.2015.06.006

1878-3686

Sara C. Meyer, Matthew D. Keller, Sophia Chiu, Priya Koppikar, Olga A. Guryanova, Franck Rapaport, Ke Xu, Katia Manova, Dmitry Pankov, Richard J. O’Reilly, Maria Kleppe, Anna Sophia McKenney, Alan H. Shih, Kaitlyn Shank, Jihae Ahn, Eftymia Papalexi, Barbara Spitzer, Nick Socci, Agnès Viale, Emeline Mandon, Nicolas Ebel, Rita Andraos, Joëlle Rubert, Ernesta Dammassa, Vincent Romanet, Arno Dölemeyer, Michael Zender, Melanie Heinlein, Raajit K. Rampal, Rona Singer Weinberg, Ronald Hoffman, William R. Sellers, Francesco Hofmann, Masato Murakami, Fabienne Baffert, Christoph Gaul, Thomas Radimerski, Ross L. Levine,

Acute Myeloid Leukemia Research

Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to 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 is a viable therapeutic approach for MPN patients.