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Cancer Discov. 2019 Nov 26. pii: CD-19-0209. doi: 10.1158/2159-8290.CD-19-0209. [Epub ahead of print]

Resistance mechanisms to SYK inhibition in acute myeloid leukemia.

Author information

1
Pediatric Oncology, Dana-Farber Cancer Institute.
2
Pediatric Oncology, DFCI.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute.
4
Genetic Perturbation Platform, Broad Institute of Harvard and MIT.
5
Hematology/Oncology, University Hospital Frankfurt.
6
Department of Hematology/Oncology, Goethe University.
7
Gilead Sciences.
8
Department of Internal Medicine/ Division of Hematology, Ohio State University.
9
Division of Hematology, Department of Medicine, The Ohio State University.
10
Genetic Perturbation Platform, Broad Institute of Massachusetts Institute of Technology and Harvard.
11
Department of Medicine II, Hematology/Oncology,, Goethe University Frankfurt.
12
Department of Pediatric Oncology, Dana-Farber Cancer Institute kimberly_stegmaier@dfci.harvard.edu.

Abstract

Spleen tyrosine kinase (SYK) is a non-mutated 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 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.

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