PuSH - Publikationsserver des Helmholtz Zentrums München

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)
Postprint DOI
Open Access Green
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.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Bcl-2 Inhibition; Open-label; Resistance; Cells; Multicenter; Decitabine; Aml
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Quellenangaben Band: 140, Heft: 24, Seiten: 2594–2610 Artikelnummer: , Supplement: ,
Verlag American Society of Hematology
Verlagsort 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Förderungen Universitätsklinikum Heidelberg
Deutsche Krebshilfe
Bundesministerium für Bildung und Forschung
Universität Heidelberg
Deutsche Forschungsgemeinschaft
Wilhelm Sander-Stiftung
Mildred Scheel Doctoral Program of German Cancer Aid