Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms.
The discovery of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of Janus kinase (JAK) inhibitors for treatment of MPN. These inhibitors improve constitutional symptoms and splenomegaly but do not significantly reduce mutant allele burden in patients. We recently showed that chronic exposure to JAK inhibitors results in inhibitor persistence via JAK2 transactivation and persistent JAK-signal transducer and activator of transcription signaling. We performed genetic and pharmacologic studies to determine whether improved JAK2 inhibition would show increased efficacy in MPN models and primary samples. Jak2 deletion in vivo led to profound reduction in disease burden not seen with JAK inhibitors, and deletion of Jak2 following chronic ruxolitinib therapy markedly reduced mutant allele burden. This demonstrates that JAK2 remains an essential target in MPN cells that survive in the setting of chronic JAK inhibition. Combination therapy with the heat shock protein 90 (HSP90) inhibitor PU-H71 and ruxolitinib reduced total and phospho-JAK2 and achieved more potent inhibition of downstream signaling than ruxolitinib monotherapy. Combination treatment improved blood counts, spleen weights, and reduced bone marrow fibrosis compared with ruxolitinib alone. These data suggest alternate approaches that increase JAK2 targeting, including combination JAK/HSP90 inhibitor therapy, are warranted in the clinical setting.
Human Oncology and Pathogenesis Program.
Neha
N
Bhagwat
Priya
P
Koppikar
Matthew
M
Keller
Sachie
S
Marubayashi
Kaitlyn
K
Shank
Raajit
R
Rampal
Jun
J
Qi
Maria
M
Kleppe
Hardik J
HJ
Patel
Smit K
SK
Shah
Tony
T
Taldone
James E
JE
Bradner
Gabriela
G
Chiosis
Ross L
RL
Levine
D019943:Amino Acid Substitution; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019046:Bone Marrow Neoplasms / Q000188:drug therapy; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003131:Combined Modality Therapy; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods*; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D053628:Receptors, Thrombopoietin / Q000235:genetics; D016896:Treatment Outcome
D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2