title: The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival.
abstract: IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138(+) cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. ascuto@coh.org
authors.forename: A
authors.initials: A
authors.lastname: Scuto
authors.forename: P
authors.initials: P
authors.lastname: Krejci
authors.forename: L
authors.initials: L
authors.lastname: Popplewell
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Kujawski
authors.forename: C
authors.initials: C
authors.lastname: Kowolik
authors.forename: H
authors.initials: H
authors.lastname: Xin
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Kretzner
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: W R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: Y
authors.initials: Y
authors.lastname: Yen
authors.forename: S
authors.initials: S
authors.lastname: Forman
authors.forename: R
authors.initials: R
authors.lastname: Jove
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056742:Cyclin D2 / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C545606:AZD 1480; D056742:Cyclin D2; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D051498:Receptor, Fibroblast Growth Factor, Type 3; D053614:Janus Kinase 2