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

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; Agnes Viale; Emeline Mandon; Nicolas Ebel; Rita Andraos; Joëlle Rubert; Ernesta Dammassa; Vincent Romanet; Arno Dölemeyer; Michael Zender; Melanie Heinlein; Raajit Rampal; Rona Singer Weinberg; Ronald Hoffman; William R. Sellers; Francesco Hofmann; Masato Murakami; Fabienne Baffert; Christoph Gaul; Thomas Radimerski; Ross L. Levine

doi:10.1016/j.ccell.2015.06.006

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

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, Agnes Viale, Emeline MandonNicolas Ebel, Rita Andraos, Joëlle Rubert, Ernesta Dammassa, Vincent Romanet, Arno Dölemeyer, Michael Zender, Melanie Heinlein, Raajit Rampal, Rona Singer Weinberg, Ronald Hoffman, William R. Sellers, Francesco Hofmann, Masato Murakami, Fabienne Baffert, Christoph Gaul, Thomas Radimerski, Ross L. Levine

Research output: Contribution to journal › Article › peer-review

128 Scopus citations

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.

Original language	English
Pages (from-to)	15-28
Number of pages	14
Journal	Cancer Cell
Volume	28
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2015.06.006
State	Published - 13 Jul 2015

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Meyer, S. C., Keller, M. D., Chiu, S., Koppikar, P., Guryanova, O. A., Rapaport, F., Xu, K., Manova, K., Pankov, D., O'Reilly, R. J., Kleppe, M., McKenney, A. S., Shih, A. H., Shank, K., Ahn, J., Papalexi, E., Spitzer, B., Socci, N., Viale, A., ... 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), 15-28. https://doi.org/10.1016/j.ccell.2015.06.006

@article{c080bc245b704ad2a9849ce7196f0664,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = jul,

day = "13",

doi = "10.1016/j.ccell.2015.06.006",

language = "English",

volume = "28",

pages = "15--28",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

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Meyer, SC, Keller, MD, Chiu, S, Koppikar, P, Guryanova, OA, Rapaport, F, Xu, K, Manova, K, Pankov, D, O'Reilly, RJ, Kleppe, M, McKenney, AS, Shih, AH, Shank, K, Ahn, J, Papalexi, E, Spitzer, B, Socci, N, Viale, A, Mandon, E, Ebel, N, Andraos, R, Rubert, J, Dammassa, E, Romanet, V, Dölemeyer, A, Zender, M, Heinlein, M, Rampal, R, Weinberg, RS, Hoffman, R, Sellers, WR, Hofmann, F, Murakami, M, Baffert, F, Gaul, C, Radimerski, T & Levine, RL 2015, 'CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms', Cancer Cell, vol. 28, no. 1, pp. 15-28. https://doi.org/10.1016/j.ccell.2015.06.006

TY - JOUR

T1 - CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

AU - Meyer, Sara C.

AU - Keller, Matthew D.

AU - Chiu, Sophia

AU - Koppikar, Priya

AU - Guryanova, Olga A.

AU - Rapaport, Franck

AU - Xu, Ke

AU - Manova, Katia

AU - Pankov, Dmitry

AU - O'Reilly, Richard J.

AU - Kleppe, Maria

AU - McKenney, Anna Sophia

AU - Shih, Alan H.

AU - Shank, Kaitlyn

AU - Ahn, Jihae

AU - Papalexi, Eftymia

AU - Spitzer, Barbara

AU - Socci, Nick

AU - Viale, Agnes

AU - Mandon, Emeline

AU - Ebel, Nicolas

AU - Andraos, Rita

AU - Rubert, Joëlle

AU - Dammassa, Ernesta

AU - Romanet, Vincent

AU - Dölemeyer, Arno

AU - Zender, Michael

AU - Heinlein, Melanie

AU - Rampal, Raajit

AU - Weinberg, Rona Singer

AU - Hoffman, Ronald

AU - Sellers, William R.

AU - Hofmann, Francesco

AU - Murakami, Masato

AU - Baffert, Fabienne

AU - Gaul, Christoph

AU - Radimerski, Thomas

AU - Levine, Ross L.

PY - 2015/7/13

Y1 - 2015/7/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937426733&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2015.06.006

DO - 10.1016/j.ccell.2015.06.006

M3 - Article

C2 - 26175413

AN - SCOPUS:84937426733

SN - 1535-6108

VL - 28

SP - 15

EP - 28

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

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

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