Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1
Year: 2022
Type: article
Abstract: 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.
Source: Blood
Authors: Maike Janssen, Christina Schmidt, Peter-Martin Bruch, Maximilian F. Blank, Christian Rohde, Alexander Waclawiczek, Daniel Heid, Simon Renders, Stefanie Göllner, Lisa Vierbaum, Birgit Besenbeck, Sophie A. Herbst, Mareike Knoll, Carolin Kolb, Adriana Przybylla, Katharina Weidenauer, Anne Kathrin Ludwig, Margarete Fabre, Muxin Gu, Richard F. Schlenk, Friedrich Stölzel, Martin Bornhäuser, Christoph Röllig, Uwe Platzbecker, Claudia Baldus, Hubert Serve, Tim Sauer, Simon Raffel, Caroline Pabst, George Vassiliou, Binje Vick, Irmela Jeremias, Andreas Trumpp, Jeroen Krijgsveld, Carsten Müller-Tidow, Sascha Dietrich
Institutions: Heidelberg University, University Hospital Heidelberg, European Molecular Biology Laboratory, European Molecular Biology Laboratory, German Cancer Research Center, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Wellcome Sanger Institute, University Hospital Carl Gustav Carus, Technische Universität Dresden, University Hospital Leipzig, Leipzig University, University Hospital Schleswig-Holstein, Goethe University Frankfurt, University Hospital Frankfurt, Helmholtz Munich, Deutsches Konsortium für Translationale Krebsforschung, Ludwig-Maximilians-Universität München
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G2574849365, G3548141514, Exvivo Modellierung der LymphknotenMikroumgebung und deren Einfluss auf das Medikamentenansprechen, SFB 873: Selbsterneuerung und Differenzierung von Stammzellen, MSCoreSys-Forschungskern: SMART-CARE - Ein systemmedizinischer Ansatz zur Stratifizierung des Rückfalls von Krebserkrankungen, Teilprojekt A, G817841614
OpenAlex ID: W4286241304