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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Meyer
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Keller
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Chiu
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Koppikar
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Guryanova
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pankov
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anna Sophia
authors.initials: AS
authors.lastname: McKenney
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Shih
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Shank
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jihae
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eftymia
authors.initials: E
authors.lastname: Papalexi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Spitzer
authors.affiliation: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Socci
authors.affiliation: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Emeline
authors.initials: E
authors.lastname: Mandon
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ebel
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Rita
authors.initials: R
authors.lastname: Andraos
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rubert
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Ernesta
authors.initials: E
authors.lastname: Dammassa
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Arno
authors.initials: A
authors.lastname: Dölemeyer
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Zender
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Heinlein
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: New York Blood Center, New York, NY 10065, USA.
authors.forename: Rona Singer
authors.initials: RS
authors.lastname: Weinberg
authors.affiliation: Department of Medicine, Mount Sinai Hospital, New York, NY 10029, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baffert
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gaul
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland. Electronic address: thomas.radimerski@novartis.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: leviner@mskcc.org.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; C507924:JAK2 protein, human; D053614:Janus Kinase 2