Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia
| Autor: | Arati V. Rao, Thomas Oellerich, S. Haihua Chu, Alison Walker, Anjali Cremer, Federica Piccioni, Amy Goodale, Gabriela Alexe, James S. Blachly, Björn Häupl, Linda Ross, Elizabeth S. Frank, Amanda L. Robichaud, John C. Byrd, Scott A. Armstrong, Yana Pikman, Jana M. Ellegast, Kimberly Stegmaier, Sebastian Mohr |
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| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Indazoles Myeloid MAP Kinase Signaling System Primary Cell Culture Syk Protein Tyrosine Phosphatase Non-Receptor Type 11 Drug resistance Protein tyrosine phosphatase Article Mice Open Reading Frames Clinical Trials Phase II as Topic Cell Line Tumor hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols Animals Humans Syk Kinase Medicine Protein Kinase Inhibitors Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Clinical Trials Phase I as Topic Gene Expression Regulation Leukemic business.industry Kinase Diphenylamine Myeloid leukemia Drug Synergism hemic and immune systems medicine.disease Xenograft Model Antitumor Assays Leukemia Myeloid Acute Leukemia medicine.anatomical_structure Oncology Drug Resistance Neoplasm Pyrazines Benzamides Mutation Mutagenesis Site-Directed Cancer research Female business |
| Zdroj: | Cancer Discov |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | Spleen tyrosine kinase (SYK) is a nonmutated therapeutic target in acute myeloid leukemia (AML). Attempts to exploit SYK therapeutically in AML have shown promising results in combination with chemotherapy, likely reflecting induced mechanisms of resistance to single-agent treatment in vivo. We conducted a genome-scale open reading frame (ORF) resistance screen and identified activation of the RAS–MAPK–ERK pathway as one major mechanism of resistance to SYK inhibitors. This finding was validated in AML cell lines with innate and acquired resistance to SYK inhibitors. Furthermore, patients with AML with select mutations activating these pathways displayed early resistance to SYK inhibition. To circumvent SYK inhibitor therapy resistance in AML, we demonstrate that a MEK and SYK inhibitor combination is synergistic in vitro and in vivo. Our data provide justification for use of ORF screening to identify resistance mechanisms to kinase inhibitor therapy in AML lacking distinct mutations and to direct novel combination-based strategies to abrogate these. Significance: The integration of functional genomic screening with the study of mechanisms of intrinsic and acquired resistance in model systems and human patients identified resistance to SYK inhibitors through MAPK signaling in AML. The dual targeting of SYK and the MAPK pathway offers a combinatorial strategy to overcome this resistance. This article is highlighted in the In This Issue feature, p. 161 |
| Databáze: | OpenAIRE |
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