title: Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition.
abstract: Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Weigert
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
authors.forename: Liat
authors.initials: L
authors.lastname: Bird
authors.forename: Nadja
authors.initials: N
authors.lastname: Kopp
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Diederik
authors.initials: D
authors.lastname: van Bodegom
authors.forename: Angela V
authors.initials: AV
authors.lastname: Toms
authors.forename: Sachie
authors.initials: S
authors.lastname: Marubayashi
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.forename: Michael
authors.initials: M
authors.lastname: McKeown
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Paranal
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.forename: Christoph
authors.initials: C
authors.lastname: Gaul
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.forename: Ralph
authors.initials: R
authors.lastname: Tiedt
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ebel
authors.forename: Emeline
authors.initials: E
authors.lastname: Evrot
authors.forename: Alain
authors.initials: A
authors.lastname: De Pover
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Régnier
authors.forename: Dirk
authors.initials: D
authors.lastname: Erdmann
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baffert
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008156:Luciferases; D051379:Mice; D008807:Mice, Inbred BALB C; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*; D055114:X-Ray Microtomography
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C498762:CRLF2 protein, human; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D012118:Resorcinols; D008156:Luciferases; D053614:Janus Kinase 2