Evaluation of the In Vitro and In Vivo Efficacy of the JAK Inhibitor AZD1480 against JAK-Mutated Acute Lymphoblastic Leukemia
| Autor: | Kathryn Evans, Raushan T. Kurmasheva, Cheryl L. Willman, Lauryn S. Bracken, Richard B. Lock, Hernan Carol, Peter J. Houghton, Keith C.S. Sia, Mignon L. Loh, Charles G. Mullighan, Santi Suryani, Stephen P. Hunger, Catherine A. Billups, Kathryn G. Roberts, Malcolm A. Smith, I-Ming Chen, Richard C. Harvey, Philipp A. Dietrich |
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| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Cell Survival MAP Kinase Signaling System Biopsy Pharmacology Article Mice In vivo medicine Animals Humans Molecular Targeted Therapy Child Protein Kinase Inhibitors Genetic Association Studies Janus Kinases Gene Expression Regulation Leukemic business.industry MEK inhibitor Precursor Cell Lymphoblastic Leukemia-Lymphoma Xenograft Model Antitumor Assays In vitro Gene expression profiling Pyrimidines Treatment Outcome Cell killing medicine.anatomical_structure Oncology Mutation Selumetinib Pyrazoles Benzimidazoles Bone marrow Janus kinase business |
| Zdroj: | Molecular Cancer Therapeutics. 14:364-374 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-14-0647 |
| Popis: | 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. Mol Cancer Ther; 14(2); 364–74. ©2014 AACR. |
| Databáze: | OpenAIRE |
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