PuSH - Publikationsserver des Helmholtz Zentrums München: Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1.

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Janssen, M.* ; Schmidt, C.* ; Bruch, P.M.* ; Blank, M.F.* ; Rohde, C.* ; Waclawiczek, A.* ; Heid, D.* ; Renders, S.* ; Göllner, S.* ; Vierbaum, L.* ; Besenbeck, B.* ; Herbst, S.A.* ; Knoll, M.* ; Kolb, C.* ; Przybylla, A.* ; Weidenauer, K.* ; Ludwig, A.K.* ; Fabre, M.* ; Gu, M.* ; Schlenk, R.F.* ; Stölzel, F.* ; Bornhäuser, M.* ; Röllig, C.* ; Platzbecker, U.* ; Baldus, C.* ; Serve, H.* ; Sauer, T.* ; Raffel, S.* ; Pabst, C.* ; Vassiliou, G.S.* ; Vick, B. ; Jeremias, I. ; Trumpp, A.* ; Krijgsveld, J.* ; Müller-Tidow, C.* ; Dietrich, S.*

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

Blood 140, 2594–2610 (2022)

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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.

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