| Literature DB >> 26175413 |
Sara C Meyer1, Matthew D Keller1, Sophia Chiu1, Priya Koppikar1, Olga A Guryanova1, Franck Rapaport1, Ke Xu2, Katia Manova2, Dmitry Pankov3, Richard J O'Reilly3, Maria Kleppe1, Anna Sophia McKenney1, Alan H Shih1, Kaitlyn Shank1, Jihae Ahn1, Eftymia Papalexi1, Barbara Spitzer1, Nick Socci4, Agnes Viale4, Emeline Mandon5, Nicolas Ebel5, Rita Andraos5, Joëlle Rubert5, Ernesta Dammassa5, Vincent Romanet5, Arno Dölemeyer5, Michael Zender5, Melanie Heinlein5, Raajit Rampal6, Rona Singer Weinberg7, Ronald Hoffman8, William R Sellers9, Francesco Hofmann5, Masato Murakami5, Fabienne Baffert5, Christoph Gaul5, Thomas Radimerski10, Ross L Levine11.
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.Entities:
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Year: 2015 PMID： 26175413 PMCID： PMC4503933 DOI： 10.1016/j.ccell.2015.06.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743