Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia
| Autor: | Jose A. Cancelas, H. Leighton Grimes, Sara Rohrabaugh, Muhammad F. Bouso, James C. Mulloy, Zachary Kincaid, Zain Siddiqui, Ahmed Gomaa, Mohammad Azam, Ming Xu, Meenu Kesarwani, Erika Huber, Kakajan Komurov, Tahir Latif |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Male Neoplasm Residual medicine.drug_class Blotting Western Apoptosis Mice Transgenic Pharmacology Biology Genes abl Real-Time Polymerase Chain Reaction General Biochemistry Genetics and Molecular Biology Tyrosine-kinase inhibitor Article 03 medical and health sciences Mice Cancer stem cell hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive medicine Animals Humans Progenitor cell Protein Kinase Inhibitors Tumor Stem Cell Assay Cell Proliferation Mice Knockout Oncogene Kinase Gene Expression Profiling Myeloid leukemia Dual Specificity Phosphatase 1 General Medicine Neoplasms Experimental Middle Aged medicine.disease Flow Cytometry Minimal residual disease 3. Good health Leukemia 030104 developmental biology Drug Resistance Neoplasm Cancer research Imatinib Mesylate Female Proto-Oncogene Proteins c-fos Neoplasm Transplantation |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X |
| Popis: | Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers. |
| Databáze: | OpenAIRE |
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