Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Sep;149(11):9451-9459.
doi: 10.1007/s00432-023-04752-9. Epub 2023 Apr 27.

Targeting the undruggable: menin inhibitors ante portas

Wolfram C M Dempke  1   2 , Maximilian Desole  3 , Patrizia Chiusolo  4 , Simona Sica  4 , Martin Schmidt-Hieber  3
Affiliations
Review

Targeting the undruggable: menin inhibitors ante portas

Wolfram C M Dempke et al. J Cancer Res Clin Oncol. 2023 Sep.

Abstract

Acute myeloid leukaemias harbouring a rearrangement of the mixed lineage leukaemia gene (MLL) are aggressive haematopoietic malignancies that relapse early and have a poor prognosis (event-free survival less than 50%). Menin is a tumour suppressor, however, in MLL-rearranged leukaemias it functions as a co-factor which is mandatory for the leukaemic transformation by interaction with the N-terminal part of MLL, which is maintained in all MLL-fusion proteins. Inhibition of menin blocks leukaemogenesis and leads to differentiation and, in turn, to apoptosis of leukaemic blasts. Furthermore, nucleophosmin 1 (NPM1) binds to specific chromatin targets, which are co-occupied by MLL, and menin inhibition has been shown to trigger degradation of mNPM1 resulting in a rapid decrease in gene expression and activating histone modifications. Therefore, disruption of the menin-MLL axis blocks leukaemias driven by NPM1 mutations for which the expression of menin-MLL target genes (e.g., MEIS1, HOX etc.) is essential. To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. In the revumenib phase I/II AUGMENT-101 trial (N = 68) with very heavily pretreated AML patients the ORR was 53% with a CR rate of 20%. The ORR in patients harbouring MLL rearrangement of mNPM1 was 59%. Patients who achieved a response had a mOS of 7 months. Similar results have been reported for ziftomenib in the phase I/II COMET-001 trial. ORR was 40% and CRc was 35% in AML patients with mNPM1. However, outcome was worse in AML patients with a MLL rearrangement (ORR 16.7%, CRc 11%). Differentiation syndrome was a notable adverse event. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

Keywords: AML; Clinical trials; MLL rearrangement; Menin inhibitors; NPM1.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Banday S, Faroog Z, Ganai SA, Altaf M (2020) Therapeutic strategies against hDOT1L as a potential drug target in MLL-arranged leukemias. Clin Epigenet 12:73 - DOI
    1. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV et al (2011) MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOTL1. Cancer Cell 20:66–78 - DOI - PubMed - PMC
    1. Burrows F, Wu T, Kessler L, Shuangwei L, Zhang J, Zarrinkar P et al (2017) A novel small molecule menin-MLL inhibitor for potential treatment of MLL-rearranged leukemias and NPM1/DNMT3A-mutant AML. Mol Targets Cancer Ther 17(Suppl 1):abstract LB-A27
    1. Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN et al (2012) Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701). A randomized, open-label, phase 3 study. Lancet 379:1508–1516 - DOI - PubMed
    1. Chen YX, Yan J, Keeshan K, Tubbs AT, Wang H, Silva A (2006) The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. Proc Natl Acad Sci USA 103:1018–1023 - DOI - PubMed - PMC

MeSH terms

Substances

LinkOut - more resources