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 |
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Sprache: | eng |
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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.
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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 |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood.2021014241 |