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

Meyer, S. C. and Keller, M. D. and Chiu, S. and Koppikar, P. and Guryanova, O. A. and Rapaport, F. and Xu, K. and Manova, K. and Pankov, D. and O'Reilly, R. J. and Kleppe, M. and McKenney, A. S. and Shih, A. H. and Shank, K. and Ahn, J. and Papalexi, E. and Spitzer, B. and Socci, N. and Viale, A. and Mandon, E. and Ebel, N. and Andraos, R. and Rubert, J. and Dammassa, E. and Romanet, V. and Dolemeyer, A. and Zender, M. and Heinlein, M. and Rampal, R. and Weinberg, R. S. and Hoffman, R. and Sellers, W. R. and Hofmann, F. and Murakami, M. and Baffert, F. and Gaul, C. and Radimerski, T. and Levine, R. L.. (2015) CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms. Cancer Cell, 28 (1). pp. 15-28.

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Official URL: https://edoc.unibas.ch/62360/

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Abstract

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.

Faculties and Departments:	03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Myeloid Malignancies (Meyer S)
UniBasel Contributors:	Meyer, Sara C.
Item Type:	Article, refereed
Article Subtype:	Research Article
e-ISSN:	1878-3686
Note:	Publication type according to Uni Basel Research Database: Journal article
Related URLs:	Green Open Access
Identification Number:	doi: 10.1016/j.ccell.2015.06.006 pmid: 26175413
Last Modified:	19 Nov 2018 17:46
Deposited On:	19 Nov 2018 17:46

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