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

Janssen, Maike; Schmidt, Christina; Bruch, Peter-Martin; Blank, Maximilian F.; Rohde, Christian; Waclawiczek, Alexander; Heid, Daniel; Renders, Simon; Goellner, Stefanie; Vierbaum, Lisa; Besenbeck, Birgit; Herbst, Sophie A.; Knoll, Mareike; Kolb, Carolin; Przybylla, Adriana; Weidenauer, Katharina; Ludwig, Anne Kathrin; Fabre, Margarete; Gu, Muxin; Schlenk, Richard F.; Stoelzel, Friedrich; Bornhaeuser, Martin; Roellig, Christoph; Platzbecker, Uwe; Baldus, Claudia; Serve, Hubert; Sauer, Tim; Raffel, Simon; Pabst, Caroline; Vassiliou, George; Vick, Binje; Jeremias, Irmela; Trumpp, Andreas; Krijgsveld, Jeroen; Mueller-Tidow, Carsten und Dietrich, Sascha (2022): Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1. In: Blood, Bd. 140, Nr. 24: S. 2594-2610

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 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-4971
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 122491522
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 464596535