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Supplementary Figures from Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia

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posted on 2023-04-03, 22:26 authored by Anjali Cremer, Jana M. Ellegast, Gabriela Alexe, Elizabeth S. Frank, Linda Ross, S. Haihua Chu, Yana Pikman, Amanda Robichaud, Amy Goodale, Björn Häupl, Sebastian Mohr, Arati V. Rao, Alison R. Walker, James S. Blachly, Federica Piccioni, Scott A. Armstrong, John C. Byrd, Thomas Oellerich, Kimberly Stegmaier

Fig. S1: Characterization of effects of Entospletinib in AML in vitro and in vivo, Fig. S2: Genome-scale lentiviral ORFeome library screen identifies drivers of entospletinib resistance in AML.; Fig. S3: Viability analysis with increasing concentrations of PRT062067; Fig. S4: Characterization of a MV4-11 cell line with acquired resistance to entospletinib; Fig. S5: PTPN11 mutants confer resistance to entospletinib in AML; Fig S6: Combination of a MEK-Inhibitor and a SYK-Inhibitor is synergistic in in vitro AML models; Fig. S7: Combination of a MEK inhibitor and a SYK inhibitor shows no toxicity in healthy mice

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ARTICLE 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. 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

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