title: Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia.
abstract: Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAK). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient-derived xenografts were established in immunodeficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The antileukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK-mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAK-mutated ALL.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Santi
authors.initials: S
authors.lastname: Suryani
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Lauryn S
authors.initials: LS
authors.lastname: Bracken
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Keith C S
authors.initials: KC
authors.lastname: Sia
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Evans
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Dietrich
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Roberts
authors.affiliation: Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.affiliation: Department of Pediatrics, University of California at San Francisco, San Francisco, California.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: University of Colorado Denver School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: CTEP/NCI, Bethesda, Maryland.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia. rlock@ccia.unsw.edu.au.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001706:Biopsy; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D056726:Genetic Association Studies; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C545606:AZD 1480; C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D053612:Janus Kinases