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Cancer Discov DOI:10.1158/2159-8290.CD-19-0209

Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia.

Publication TypeJournal Article
Year of Publication2020
AuthorsCremer, A, Ellegast, JM, Alexe, G, Frank, ES, Ross, L, S Chu, H, Pikman, Y, Robichaud, A, Goodale, A, Häupl, B, Mohr, S, Rao, AV, Walker, AR, Blachly, JS, Piccioni, F, Armstrong, SA, Byrd, JC, Oellerich, T, Stegmaier, K
JournalCancer Discov
Volume10
Issue2
Pages214-231
Date Published2020 Feb
ISSN2159-8290
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 . 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 and . 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..

DOI10.1158/2159-8290.CD-19-0209
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31771968?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID31771968
PubMed Central IDPMC7058374
Grant ListK08 CA222684 / CA / NCI NIH HHS / United States
P50 CA206963 / CA / NCI NIH HHS / United States
R35 CA197734 / CA / NCI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States