1. CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms
- Author
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Fabienne Baffert, Nick Socci, Joëlle Rubert, Barbara Spitzer, Michael Zender, Nicolas Ebel, Efthymia Papalexi, Ernesta Dammassa, Anna Sophia McKenney, Ronald Hoffman, Alan H. Shih, William R. Sellers, Ross L. Levine, Emeline Mandon, Rita Andraos, Sophia Chiu, Ke Xu, Raajit K. Rampal, Matthew D. Keller, Dmitry Pankov, Richard J. O'Reilly, Melanie Heinlein, Franck Rapaport, Jihae Ahn, Maria Kleppe, Sara C. Meyer, Francesco Hofmann, Arno Dölemeyer, Priya Koppikar, Masato Murakami, Christoph Gaul, Olga A. Guryanova, Vincent Romanet, Kaitlyn Shank, Thomas Radimerski, Katia Manova, Rona Singer Weinberg, and Agnes Viale
- Subjects
Cancer Research ,Molecular Sequence Data ,Antineoplastic Agents ,medicine.disease_cause ,Article ,Mice ,Myeloproliferative Disorders ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptor ,Protein Kinase Inhibitors ,Myeloproliferative neoplasm ,Cell Proliferation ,Mutation ,Janus kinase 2 ,biology ,Sequence Analysis, RNA ,Cell growth ,food and beverages ,Cell Biology ,Janus Kinase 2 ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Mice, Inbred C57BL ,Pyrimidines ,Oncology ,Cell culture ,Benzamides ,Immunology ,biology.protein ,Cancer research ,Signal transduction ,Receptors, Thrombopoietin ,Signal Transduction - Abstract
SummaryAlthough 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.
- Published
- 2015