Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase-Driven Leukemias and Other Malignancies
| Autor: | Keith W. Pratz, Hayley S Ma, Michelle A. Rudek, Donald Small, Li Li, Richard J. Jones, Alice Can Ran Qin, J. Kyle Bruner, Mark J. Levis, Christine A. Pratilas |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Niacinamide Cancer Research Myeloid MAP Kinase Signaling System HL-60 Cells Mice SCID Biology Article 03 medical and health sciences Mice Random Allocation Mice Inbred NOD hemic and lymphatic diseases Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Tyrosine Protein Kinase Inhibitors Cell Proliferation Phenylurea Compounds Diphenylamine Myeloid leukemia Sorafenib medicine.disease Xenograft Model Antitumor Assays Leukemia Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Oncology Immunology Cancer cell Benzamides Cancer research Female K562 Cells Tyrosine kinase K562 cells |
| Zdroj: | Cancer research. 77(20) |
| ISSN: | 1538-7445 |
| Popis: | FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia (AML). We hypothesized that FLT3/internal tandem duplication (ITD) leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here, we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared with either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase–driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer, and BCR–ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase–driven cancers associated with reactivation of ERK signaling in response to targeted inhibition. Cancer Res; 77(20); 5554–63. ©2017 AACR. |
| Databáze: | OpenAIRE |
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