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Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia.
- Source :
-
Cancer discovery [Cancer Discov] 2020 Feb; Vol. 10 (2), pp. 214-231. Date of Electronic Publication: 2019 Nov 26. - Publication Year :
- 2020
-
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 .<br /> (©2019 American Association for Cancer Research.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 10
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 31771968
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-19-0209