Academic Journal
Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia
| العنوان: | Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia |
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| المؤلفون: | Suryani, S, Bracken, LS, Harvey, RC, Sia, KCS, Carol, H, Chen, IM, Evans, K, Dietrich, PA, Roberts, KG, Kurmasheva, RT, Billups, CA, Mullighan, CG, Willman, CL, Loh, ML, Hunger, SP, Houghton, PJ, Smith, MA, Lock, RB |
| المصدر: | urn:ISSN:1535-7163 ; urn:ISSN:1538-8514 ; Molecular Cancer Therapeutics, 14, 2, 364-374 |
| بيانات النشر: | American Association for Cancer Research (AACR) |
| سنة النشر: | 2015 |
| المجموعة: | UNSW Sydney (The University of New South Wales): UNSWorks |
| مصطلحات موضوعية: | 31 Biological Sciences, 32 Biomedical and Clinical Sciences, 3202 Clinical Sciences, Childhood Leukemia, Rare Diseases, Hematology, Pediatric Cancer, Human Genome, Genetics, Biotechnology, Pediatric, Cancer, 5.1 Pharmaceuticals, Animals, Benzimidazoles, Biopsy, Cell Survival, Child, Gene Expression Regulation, Leukemic, Genetic Association Studies, Humans, Janus Kinases, MAP Kinase Signaling System, Mice, Molecular Targeted Therapy, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein Kinase Inhibitors, Pyrazoles |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| Relation: | http://purl.org/au-research/grants/nhmrc/APP1059804; http://hdl.handle.net/1959.4/unsworks_40506 |
| DOI: | 10.1158/1535-7163.MCT-14-0647 |
| الاتاحة: | http://hdl.handle.net/1959.4/unsworks_40506 https://unsworks.unsw.edu.au/bitstreams/7138f956-d7cd-40d8-bbfe-7ded96f20980/download https://unsworks.unsw.edu.au/bitstreams/6fb07889-4a07-482d-a5ef-c88a7d587565/download https://doi.org/10.1158/1535-7163.MCT-14-0647 |
| Rights: | open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0/ ; free_to_read |
| رقم الانضمام: | edsbas.DCA0AE02 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1158/1535-7163.MCT-14-0647 |
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