Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1

•High-throughput drug screening identified gilteritinib and venetoclax as a highly synergistic drug combination in FLT3 wild-type AML.•Gilteritinib-venetoclax suppressed MCL-1 and decreased venetoclax-azacitidine–resistant FLT3 wild-type AML viability in vitro and in vivo. [Display omitted] BCL-2 in...

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Veröffentlicht in:Blood 2022-12, Vol.140 (24), p.2594-2610
Hauptverfasser: Janssen, Maike, Schmidt, Christina, Bruch, Peter-Martin, Blank, Maximilian F., Rohde, Christian, Waclawiczek, Alexander, Heid, Daniel, Renders, Simon, Göllner, Stefanie, Vierbaum, Lisa, Besenbeck, Birgit, Herbst, Sophie A., Knoll, Mareike, Kolb, Carolin, Przybylla, Adriana, Weidenauer, Katharina, Ludwig, Anne Kathrin, Fabre, Margarete, Gu, Muxin, Schlenk, Richard F., Stölzel, Friedrich, Bornhäuser, Martin, Röllig, Christoph, Platzbecker, Uwe, Baldus, Claudia, Serve, Hubert, Sauer, Tim, Raffel, Simon, Pabst, Caroline, Vassiliou, George, Vick, Binje, Jeremias, Irmela, Trumpp, Andreas, Krijgsveld, Jeroen, Müller-Tidow, Carsten, Dietrich, Sascha
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Zusammenfassung:•High-throughput drug screening identified gilteritinib and venetoclax as a highly synergistic drug combination in FLT3 wild-type AML.•Gilteritinib-venetoclax suppressed MCL-1 and decreased venetoclax-azacitidine–resistant FLT3 wild-type AML viability in vitro and in vivo. [Display omitted] BCL-2 inhibition has been shown to be effective in acute myeloid leukemia (AML) in combination with hypomethylating agents or low-dose cytarabine. However, resistance and relapse represent major clinical challenges. Therefore, there is an unmet need to overcome resistance to current venetoclax-based strategies. We performed high-throughput drug screening to identify effective combination partners for venetoclax in AML. Overall, 64 antileukemic drugs were screened in 31 primary high-risk AML samples with or without venetoclax. Gilteritinib exhibited the highest synergy with venetoclax in FLT3 wild-type AML. The combination of gilteritinib and venetoclax increased apoptosis, reduced viability, and was active in venetoclax-azacitidine–resistant cell lines and primary patient samples. Proteomics revealed increased FLT3 wild-type signaling in specimens with low in vitro response to the currently used venetoclax-azacitidine combination. Mechanistically, venetoclax with gilteritinib decreased phosphorylation of ERK and GSK3B via combined AXL and FLT3 inhibition with subsequent suppression of the antiapoptotic protein MCL-1. MCL-1 downregulation was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161, and proteasomal degradation. Gilteritinib and venetoclax were active in an FLT3 wild-type AML patient-derived xenograft model with TP53 mutation and reduced leukemic burden in 4 patients with FLT3 wild-type AML receiving venetoclax-gilteritinib off label after developing refractory disease under venetoclax-azacitidine. In summary, our results suggest that combined inhibition of FLT3/AXL potentiates venetoclax response in FLT3 wild-type AML by inducing MCL-1 degradation. Therefore, the venetoclax-gilteritinib combination merits testing as a potentially active regimen in patients with high-risk FLT3 wild-type AML. Janssen and colleagues identify increased FLT3 signaling and associated MCL1 expression as hallmarks of high-risk acute myeloid leukemia (AML) with wild-type FLT3. They provide preclinical and preliminary clinical evidence that reducing FLT3 signaling through treatment with the FLT3 inhibitor gilteritinib reduces MCL1 e
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2021014241