HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans.
JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the MPN polycythemia vera (PV) and essential thrombocytosis (ET) by disrupting JAK2 protein stability. JAK2 physically associated with both HSP90 and PU-H71 and was degraded by PU-H71 treatment in vitro and in vivo, demonstrating that JAK2 is an HSP90 chaperone client. PU-H71 treatment caused potent, dose-dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity. Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2-dependent MPN.
Marubayashi
Sachie
S
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Koppikar
Priya
P
Taldone
Tony
T
Abdel-Wahab
Omar
O
West
Nathan
N
Bhagwat
Neha
N
Caldas-Lopes
Eloisi
E
Ross
Kenneth N
KN
Gönen
Mithat
M
Gozman
Alex
A
Ahn
James H
JH
Rodina
Anna
A
Ouerfelli
Ouathek
O
Yang
Guangbin
G
Hedvat
Cyrus
C
Bradner
James E
JE
Chiosis
Gabriela
G
Levine
Ross L
RL
D000818:Animals; D052117:Benzodioxoles / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D002460:Cell Line; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D011087:Polycythemia Vera / Q000188:drug therapy; D055728:Primary Myelofibrosis / Q000188:drug therapy; D011687:Purines / Q000627:therapeutic use*; D015398:Signal Transduction; D013920:Thrombocythemia, Essential / Q000188:drug therapy; D034061:Thrombopoiesis / Q000187:drug effects
D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2