Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

Cells. 2022 Sep 3;11(17):2752. doi: 10.3390/cells11172752.

Abstract

FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.

Keywords: AZD5991; FLT3; FLT3-ITD; MRX-2843; Mcl-1; acute myeloid leukemia; gilteritinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Macrocyclic Compounds
  • Myeloid Cell Leukemia Sequence 1 Protein* / antagonists & inhibitors
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Pyrazines / pharmacology
  • fms-Like Tyrosine Kinase 3* / genetics

Substances

  • Aniline Compounds
  • AZD5991
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • gilteritinib
  • Macrocyclic Compounds
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Kinase Inhibitors
  • Pyrazines
  • MRX-2843

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (NSGC81800154 to Guan Wang), The Children’s Foundation, LaFontaine Family/U CAN-CER VIVE Foundation, Kids Without Cancer, Decerchio/Guisewite Family, Justin’s Gift, Elana Fund, Ginopolis/Karmanos Endowment, the Ring Screw Textron Endowed Chair for Pediatric Cancer Research. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or the decision to publish the results.