2. Academic Validation
  3. Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML

Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML

  • Leuk Res. 2024 Jun 24:144:107547. doi: 10.1016/j.leukres.2024.107547.
Shuangshuang Wu 1,  Fangbing Liu 2,  Yuqing Gai 2,  Jenna Carter 3,  Holly Edwards 4,  Maik Hüttemann 5,  Guan Wang 2,  Chunhuai Li 1,  Jeffrey W Taub 6,  Yue Wang 7,  Yubin Ge 8
Affiliations

Affiliations

  • 1 Department of Pediatric Hematology, The First Hospital of Jilin University, Changchun, PR China.
  • 2 National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China.
  • 3 Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA; MD/PhD Program, Wayne State University School of Medicine, Detroit, MI, USA.
  • 4 Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
  • 5 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
  • 6 Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA; Department of Pediatrics, Central Michigan University College of Medicine, Mt. Pleasant, MI, USA.
  • 7 Department of Pediatric Hematology, The First Hospital of Jilin University, Changchun, PR China. Electronic address: wang_yue@jlu.edu.cn.
  • 8 Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: gey@karmanos.org.
PMID: 38968731 DOI: 10.1016/j.leukres.2024.107547
Abstract

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 Inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases Oxidative Phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.

Keywords

Acute myeloid leukemia; Bcl-2; FLT3-ITD; MRX-2843; Venetoclax.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101549
    99.70%, MERTK/FLT3 Inhibitor