1. Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia.
- Author
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Cremer A, Ellegast JM, Alexe G, Frank ES, Ross L, Chu SH, Pikman Y, Robichaud A, Goodale A, Häupl B, Mohr S, Rao AV, Walker AR, Blachly JS, Piccioni F, Armstrong SA, Byrd JC, Oellerich T, and Stegmaier K
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzamides pharmacology, Benzamides therapeutic use, Cell Line, Tumor, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Diphenylamine analogs & derivatives, Diphenylamine pharmacology, Diphenylamine therapeutic use, Drug Resistance, Neoplasm drug effects, Drug Synergism, Female, Gene Expression Regulation, Leukemic drug effects, Humans, Indazoles pharmacology, Indazoles therapeutic use, Leukemia, Myeloid, Acute genetics, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System genetics, Mice, Mitogen-Activated Protein Kinase 1 genetics, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase Kinases metabolism, Mutagenesis, Site-Directed, Mutation, Open Reading Frames genetics, Primary Cell Culture, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Pyrazines pharmacology, Pyrazines therapeutic use, Syk Kinase metabolism, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Drug Resistance, Neoplasm genetics, Leukemia, Myeloid, Acute drug therapy, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Syk Kinase antagonists & inhibitors
- Abstract
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 ., (©2019 American Association for Cancer Research.)
- Published
- 2020
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