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

• Published in: Cancer cell 2015-07, Vol.28 (1), p.15-28
• Main Authors: Meyer, Sara C., Keller, Matthew D., Chiu, Sophia, Koppikar, Priya, Guryanova, Olga A., Rapaport, Franck, Xu, Ke, Manova, Katia, Pankov, Dmitry, O’Reilly, Richard J., Kleppe, Maria, McKenney, Anna Sophia, Shih, Alan H., Shank, Kaitlyn, Ahn, Jihae, Papalexi, Eftymia, Spitzer, Barbara, Socci, Nick, Viale, Agnes, Mandon, Emeline, Ebel, Nicolas, Andraos, Rita, Rubert, Joëlle, Dammassa, Ernesta, Romanet, Vincent, Dölemeyer, Arno, Zender, Michael, Heinlein, Melanie, Rampal, Raajit, Weinberg, Rona Singer, Hoffman, Ronald, Sellers, William R., Hofmann, Francesco, Murakami, Masato, Baffert, Fabienne, Gaul, Christoph, Radimerski, Thomas, Levine, Ross L.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Benzamides - administration & dosage; Cell Line, Tumor; Cell Proliferation - drug effects; Humans; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - genetics; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mutation; Myeloproliferative Disorders - drug therapy; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Pyrimidines - administration & dosage; Receptors, Thrombopoietin - genetics; Receptors, Thrombopoietin - metabolism; Sequence Analysis, RNA; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.06.006

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. [Display omitted] •CHZ868, a type II JAK inhibitor, reverses type I JAK inhibitor persistence•Type II JAK inhibition with CHZ868 preferentially inhibits V617F mutant versus WT JAK2•Type II JAK inhibition shows increased efficacy in preclinical MPN models•Type II JAK inhibition reduces mutant allele burden in JAK2-/MPL mutant MPN models The current clinical JAK2 inhibitors are type I kinase inhibitors that provide clinical benefits to myeloproliferative neoplasm (MPN) patients but do not reduce mutant allele burden. Meyer et al. report a type II JAK2 inhibitor that shows activity against relevant MPN models and reduces mutant allele burden.