Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia

Cancer Discov. 2020 Feb;10(2):214-231. doi: 10.1158/2159-8290.CD-19-0209. Epub 2019 Nov 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • 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 Resistance, Neoplasm / genetics*
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Indazoles / pharmacology
  • Indazoles / therapeutic use
  • Leukemia, Myeloid, Acute / drug therapy*
  • 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 / antagonists & inhibitors*
  • 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 / antagonists & inhibitors*
  • Syk Kinase / metabolism
  • Xenograft Model Antitumor Assays


  • 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine
  • Benzamides
  • Indazoles
  • Protein Kinase Inhibitors
  • Pyrazines
  • mirdametinib
  • Diphenylamine
  • SYK protein, human
  • Syk Kinase
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11