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 Felix; Rohde, Christian; Waclawiczek, Alexander; Heid, Daniel; Renders, Simon; Göllner, Stefanie; Vierbaum, Lisa; Besenbeck, Birgit; Herbst, Sophie A.; Knoll, Maximilian; Kolb, Carolin; Przybylla, Adriana; Weidenauer, Katharina; Ludwig, Anne K.; Fabre, M; Gu, Muxin; Schlenk, Richard F.; Stölzel, Friedrich; Bornhäuser, Martin; Röllig, Christoph; Platzbecker, Uwe; Baldus, Claudia D.; Serve, Hubert; Sauer, Tim; Raffel, Simon; Pabst, Caroline; Vassiliou, George S.; Vick, Binje; Jeremias, Irmela; Trumpp, Andreas; Krijgsveld, Jeroen; Müller-Tidow, Carsten; Dietrich, Sascha

doi:10.1182/blood.2021014241

Cited by 52 publications

(35 citation statements)

References 40 publications

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“…Systematic, high-throughput combination drug screens revealed that MRX-2483 most profoundly and consistently synergizes with the BCL-2 specific inhibitor, venetoclax, and to a lesser extent the pan BCL-2 inhibitors gossypol or obatoclax (48, 49) to provide anti-leukemia activity across a genotypically diverse panel of AML cell lines and primary patient samples. These findings are consistent with recent reports demonstrating synergistic interactions between venetoclax and FLT3, dual FLT3/AXL, or dual MERTK/AXL inhibitors in AML (50-52) and provide the first demonstration of synergy between a dual MERTK/FLT3 inhibitor and venetoclax in AML. Of note, MRX-2843 synergized with venetoclax in the absence of activating FLT3 mutations.…”

Section: Discussionsupporting

confidence: 92%

Constitutively synergistic multiagent drug formulations targeting MERTK, FLT3, and BCL-2 for treatment of AML

Kelvin

Jain

Thapa

et al. 2023

Preprint

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Although high-dose, multi-agent chemotherapy has improved leukemia survival rates in recent years, treatment outcomes remain poor in high-risk subsets, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in infants. Development of new, more effective therapies for these patients is therefore an urgent, unmet clinical need. To address this challenge, we developed a nanoscale combination drug formulation that exploits ectopic expression of MERTK tyrosine kinase and dependency on BCL-2 family proteins for leukemia cell survival in pediatric AML and MLL-rearranged precursor B-cell ALL (infant ALL). In a novel, high-throughput combination drug screen, the MERTK/FLT3 inhibitor MRX-2843 synergized with venetoclax and other BCL-2 family protein inhibitors to reduce AML cell density in vitro. Neural network models based on drug exposure and target gene expression were used to identify a classifier predictive of drug synergy in AML. To maximize the therapeutic potential of these findings, we developed a combination monovalent liposomal drug formulation that maintains ratiometric drug synergy in cell-free assays and following intracellular delivery. The translational potential of these nanoscale drug formulations was confirmed in a genotypically diverse set of primary AML patient samples and both the magnitude and frequency of synergistic responses were not only maintained but were improved following drug formulation. Together, these findings demonstrate a systematic, generalizable approach to combination drug screening, formulation, and development that maximizes therapeutic potential, was effectively applied to develop a novel nanoscale combination therapy for treatment of AML, and could be extended to other drug combinations or diseases in the future.

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Section: Discussionsupporting

confidence: 92%

Constitutively synergistic multiagent drug formulations targeting MERTK, FLT3, and BCL-2 for treatment of AML

Kelvin

Jain

Thapa

et al. 2023

Preprint

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“…89 Janssen and coworkers screened in vitro 654 antileukemic compounds in combination with VEN in 31 primary samples of high-risk AMLs and observed that gilteritinib exhibited the highest synergy with VEN in WT FLT3 AMLs. 90 Importantly, the VEN+gilteritinib was active in inducing apoptosis of leukemic cell lines and primary AML cells resistant to VEN+AZA. 90 Mechanistically, the VEN+gilteritinib combination decreased phosphorylation of ERK and GSK3B via combined inhibition of FLT3 and AXL, mediating suppression of the MCL1 antiapoptotic protein through induction of its proteasomal degradation.…”

Section: Flt3-mutatedmentioning

confidence: 99%

“… 90 Mechanistically, the VEN+gilteritinib combination decreased phosphorylation of ERK and GSK3B via combined inhibition of FLT3 and AXL, mediating suppression of the MCL1 antiapoptotic protein through induction of its proteasomal degradation. 90 These observations support the evaluation of VEN+gilteritinib as a potential therapeutic regimen for high-risk AML patients with FLT3 WT.…”

Section: Outcomes Of Selected Aml Subtypes Following Venetoclax-based...mentioning

confidence: 99%

“… 82 , 91 Thus, it was shown that treatment with A FLT3 inhibitor (midostaurin or gilteritinib) alone or in combination with VEN elicited a downmodulation of MCL-1 expression, seeming induced by simultaneous suppression of multiple signaling pathways, including STAT5, RAS-MAPK and PI3K-AKT. 82 , 90 The effect t of the two drugs was complementary: gilteritinib treatment reduced the binding of BIM to MCL-1 and increased the binding of BIM to BCL-2, while VEN increased the binding of BIM to MCL-1 but inhibited the binding of BIM to BCL-2. 82 , 91 Importantly, co-treatment with VEN and gilteritinib increased the binding of BIM to BAX without increasing the binding of BIM to other BCL-2 anti-apoptotic proteins.…”

Section: Outcomes Of Selected Aml Subtypes Following Venetoclax-based...mentioning

confidence: 99%

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The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Castelli¹,

Testa²

2022

Mediterr J Hematol Infect Dis

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In spite recent progresses, acute myeloid leukemia (AML) remains a disease associated with poor prognosis, particularly in older AML patients unfit to tolerate intensive chemotherapy treatment. The development and introduction in therapy of the drug Venetoclax, a potent BH3 mimetic targeting the antiaopoptotic protein BCL-2, inducing apoptosis of leukemic cells, has shown to be a promising treatment for newly diagnosed, relapsed and refractory AML patients ineligible for induction chemotherapy. Combination treatments using Ventoclax and a hypomethylating agent (azacytidine or decitabine) or low-intensity chemotherapy have shown in newly diagnosed patients variable response rates, with highly responsive patients with NPM1, IDH1-IDH2, TET2 and RUNX1 mutations and with scarcely responsive patients with FLT3, TP53 and ASXL1 mutations, complex karyotypes and secondary AMLs. Patients with refractory/relapsing disease are less responsive to Venetoclax-based regimens. However, in the majority of patients the responses have only a limited duration and development of resistance is frequently observed. Understanding mechanisms of resistance is of crucial importance for the development of new strategies and identification of rational drug combination regimens. In this context, two strategies seem to be promising: (i) triplet therapies based on the combined administration of Venetoclax, a hypomethylating agent (or low-dose chemotherapy) and an agent targeting a specific genetic alteration of leukemic cells (i.e., FLT3 inhibitors in FLT3-mutated AMLs) or an altered signaling pathway; (ii) combination therapies based on the administration of two BH3 mimetics (i.e., BCL-2 +MCL-1 mimetics) and a hypomethylating agent.

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“…Of note, combination of venetoclax and gilterinib seems to be highly synergistic in vitro and in mice xenografts through the inhibition of MCL1 and the kinase AXL. 64 This combination will probably be game-changing in the management of FLT3mut AML in the future.…”

Section: Perspectivementioning

confidence: 99%

FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile

Garciaz

Hospital

2023

OTT

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FMS-like tyrosine kinase 3 ( FLT3 ) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Approximately 30% of the adult cases harbor an internal tandem duplication ( FLT3 -ITD) and 5–10% a tyrosine kinase domain (TKD) amino acid substitution ( FLT3-TKD ). The treatment paradigm of AML patients harboring FLT3 mutations (30%) has been modified by the discovery of tyrosine kinase inhibitors. First- and second-generation inhibitors classify FLT3 inhibitors according to FLT3 specificity: first-generation FLT3 inhibitors include sorafenib and midostaurin and second-generation inhibitors are represented by quizartinib, gilteritinib and crenolanib, among others. Activity of these inhibitors depends on their mechanism of receptor binding (active vs inactive conformation) and efficacy against the FLT3-ITD and -TKD mutations (type 1 inhibitors are active both on FLT3 -ITD and TKD, whereas type 2 inhibitors are active only on FLT3 -ITD). The FLT3 inhibitors sorafenib, midostaurin, quizartinib and gilteritinib have been tested in monotherapy in several settings including refractory or relapsed AML (R/R AML), post-transplant maintenance as well as in combination with intensive chemotherapy (ICT) or non-intensity regimens. The results of published randomized studies support the use of sorafenib in a post-transplant setting (SORMAIN trial), midostaurin in combination with ICT based (RATIFY trial) and gilteritinib for R/R AML (ADMIRAL trial). Gilteritinib in combination with hypomethylating agent as well as quizartinib are not supported by solid randomized trial results for their use in FLT3-mutated AML patients.

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

Cited by 52 publications

References 40 publications

Constitutively synergistic multiagent drug formulations targeting MERTK, FLT3, and BCL-2 for treatment of AML

Constitutively synergistic multiagent drug formulations targeting MERTK, FLT3, and BCL-2 for treatment of AML

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile

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