Journal
BLOOD
Volume 140, Issue 24, Pages 2594-2610Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021014241
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Funding
- Physician Scientist Program of the University of Heidelberg
- Mildred Scheel Doctoral Program of German Cancer Aid
- German Cancer Aid (Mildred-Scheel Junior Research Centre)
- German Cancer Aid [BW70113908]
- German Research Foundation [MU1328/18-1, Sonderfor-schungsbereich 873, 122491522, 464596535]
- Federal Ministry of Education and Research (BMBF) [031L0212A]
- Wilhelm Sander Foundation [2021.145.1]
- BMBF [01ZX1506, 464596535SYMPATY]
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This study found that gilteritinib had the best synergy with venetoclax in FLT3 wild-type AML through high-throughput drug screening. The combination of gilteritinib and venetoclax increased apoptosis, reduced cell viability, and showed activity in venetoclax-azacitidine-resistant cell lines and primary patient samples.
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 anti-apoptotic protein MCL-1. MCL-1 downregulation was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161, and pro-teasomal 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.
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