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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

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

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.

Methods Mol Biol. 2005;290:13-23. (PMID: 15361652)
Genes Dev. 1999 Jun 1;13(11):1367-81. (PMID: 10364155)
Signal Transduct Target Ther. 2020 Feb 26;5(1):17. (PMID: 32296028)
JCI Insight. 2016 Mar;1(3):e85630. (PMID: 27158668)
J Clin Invest. 2010 Jun;120(6):2109-18. (PMID: 20484815)
Cancers (Basel). 2022 Jul 13;14(14):. (PMID: 35884458)
N Engl J Med. 2013 May 30;368(22):2059-74. (PMID: 23634996)
Blood Cancer J. 2021 Jun 7;11(6):111. (PMID: 34099621)
Mol Aspects Med. 2019 Dec;70:21-32. (PMID: 31623866)
Mol Cancer Ther. 2021 Nov;20(11):2207-2217. (PMID: 34518298)
Oncogene. 2013 Nov 14;32(46):5359-68. (PMID: 23474756)
Leukemia. 2019 Feb;33(2):299-312. (PMID: 30651634)
Haematologica. 2019 Nov;104(11):2225-2240. (PMID: 30819918)
Cancers (Basel). 2020 Aug 24;12(9):. (PMID: 32847115)
J Exp Clin Cancer Res. 2018 Jul 27;37(1):173. (PMID: 30053872)
Genes Dev. 2014 Jan 1;28(1):58-70. (PMID: 24395247)
Leukemia. 2014 Jul;28(7):1557-60. (PMID: 24531733)
Blood. 1996 Apr 15;87(8):3395-403. (PMID: 8605357)
Oncotarget. 2016 Jun 7;7(23):34785-99. (PMID: 27166183)
J Membr Biol. 2004 Mar 1;198(1):43-53. (PMID: 15209096)
Clin Cancer Res. 2019 Nov 15;25(22):6815-6826. (PMID: 31320594)
N Engl J Med. 2019 Oct 31;381(18):1728-1740. (PMID: 31665578)
Cell Metab. 2017 Oct 3;26(4):633-647.e7. (PMID: 28978427)
PLoS One. 2013 Nov 11;8(11):e79106. (PMID: 24244429)
Biochem Pharmacol. 2018 Feb;148:13-26. (PMID: 29208365)
Genes Dev. 2012 Jan 15;26(2):120-5. (PMID: 22279045)
Blood. 2008 Mar 1;111(5):2527-37. (PMID: 17965322)
Haematologica. 2021 Apr 01;106(4):1034-1046. (PMID: 32414851)
PLoS One. 2014 Aug 15;9(8):e105381. (PMID: 25127121)
Blood. 2002 Sep 1;100(5):1532-42. (PMID: 12176867)
Cancer. 2006 Nov 1;107(9):2099-107. (PMID: 17019734)
Oncotarget. 2017 Dec 4;9(10):8870-8886. (PMID: 29507660)
Oncogene. 2002 May 13;21(21):3414-21. (PMID: 12032779)
Blood Rev. 2020 Nov;44:100672. (PMID: 32204955)
Semin Cell Dev Biol. 2015 Jul;43:11-21. (PMID: 26277543)
J Cell Mol Med. 2018 Dec;22(12):6099-6111. (PMID: 30596398)
Blood. 2006 Feb 15;107(4):1570-81. (PMID: 16249385)
Methods. 2001 Dec;25(4):402-8. (PMID: 11846609)
Pharmacol Rev. 2006 Sep;58(3):621-81. (PMID: 16968952)
Int J Hematol. 2019 Nov;110(5):566-574. (PMID: 31432396)
J Natl Cancer Inst. 2005 Feb 2;97(3):226-31. (PMID: 15687366)
Apoptosis. 2022 Aug 9;:. (PMID: 35943677)
Nat Cell Biol. 2012 Apr 29;14(6):575-83. (PMID: 22544066)
Cell Death Differ. 2006 Sep;13(9):1423-33. (PMID: 16676004)
Hematol Oncol. 2017 Sep;35(3):350-356. (PMID: 26856970)
Haematologica. 2020 Dec 23;107(1):58-76. (PMID: 33353284)
Clin Cancer Res. 2010 Nov 15;16(22):5499-510. (PMID: 20889917)
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1259-63. (PMID: 11818574)
Sci Rep. 2017 Feb 08;7:41950. (PMID: 28176818)
Ann Hematol. 2020 Oct;99(10):2231-2242. (PMID: 32621182)
Clin Transl Oncol. 2013 Feb;15(2):87-94. (PMID: 22911553)

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

0 (Aniline Compounds)
0 (AZD5991)
EC 2.7.10.1 (FLT3 protein, human)
EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
0 (gilteritinib)
0 (Macrocyclic Compounds)
0 (MCL1 protein, human)
0 (Myeloid Cell Leukemia Sequence 1 Protein)
0 (Protein Kinase Inhibitors)
0 (Pyrazines)
0 (MRX-2843)

Date Created: 20220909 Date Completed: 20230824 Latest Revision: 20230824

20230825

PMC9455003

10.3390/cells11172752

36078163