title: Combined inhibition of Janus kinase 1/2 for the treatment of JAK2V617F-driven neoplasms: selective effects on mutant cells and improvements in measures of disease severity.
abstract: OBJECTIVE
  Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for the Philadelphia chromosome-negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy.
  
  
  METHODS
  A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight, and disease-associated inflammatory markers were measured.
  
  
  RESULTS
  INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F mutation by blocking JAK-STAT signaling and inducing apoptosis. In vivo, INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon treatment.
  
  
  CONCLUSIONS
  These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients with myeloproliferative diseases and other neoplasms associated with JAK dysregulation.
authors.affiliation: Departments of Applied Technology, Preclinical Biology, In vitro Biology, and Medicinal Chemistry, Incyte Corporation, Wilmington, DE 19880, USA.
authors.forename: Phillip C C
authors.initials: PC
authors.lastname: Liu
authors.forename: Eian
authors.initials: E
authors.lastname: Caulder
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Waeltz
authors.forename: Alex
authors.initials: A
authors.lastname: Margulis
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Mary
authors.initials: M
authors.lastname: Becker-Pasha
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Erin
authors.initials: E
authors.lastname: Crowgey
authors.forename: Gregory
authors.initials: G
authors.lastname: Hollis
authors.forename: Patrick
authors.initials: P
authors.lastname: Haley
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sparks
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.forename: James D
authors.initials: JD
authors.lastname: Rodgers
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D053613:Janus Kinase 1 / Q000235:genetics* / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D011087:Polycythemia Vera / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D053613:Janus Kinase 1; D053614:Janus Kinase 2