Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with <i>MLL</i> rearrangement or <i>NPM1</i> mutation to venetoclax
Johanna Rausch, Margarita M. Dzama, Nadezda Dolgikh, Hanna L. Stiller, Stephan Bohl, Catharina Lahrmann, Kerstin Kunz, Linda Kessler, Hakim Echchannaoui, Chun‐Wei Chen, Thomas Kindler, Konstanze Döhner, Francis Burrows, Matthias Theobald, Daniel Sasca, Michael W.M. Kühn
Abstract
Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclaxAcute myeloid leukemia (AML) represents a genetically heterogeneous group of myeloid neoplasms derived from early hematopoietic progenitors.Mutations in the NPM1 gene and chromosomal rearrangements of the gene encoding the histone 3 lysine 4 (H3K4) methyltransferase MLL (KMT2A) represent recurrent genetic abnormalities that define distinct AML subtypes and predict treatment outcomes. 1,2Both genetic alterations in AML are associated with activating a particular leukemogenic transcriptional program, including the aberrant expression of the self-renewal associated homeobox (HOX), MEIS1, and PBX3 transcription factor genes and their target genes FLT3 and BCL2. 3 The interaction of MLL with the adaptor protein menin is required for MLL-rearranged (MLL-r) leukemogenesis, 3 and we discovered that NPM1 mut AML also depends on the menin binding motif in MLL. 4 Small-molecule inhibitors that block the menin-MLL interaction cause downregulation of leukemic gene expression, induce differentiation, and have anti-leukemic ac-tivity against NPM1 mut and MLL-r leukemia models (reviewed in 5 ).Ziftomenib is one of five menin inhibitors currently assessed in clinical phase I/II trials (clinicaltrials gov.Identifiers: NCT04067336, NCT04065399, NCT05153330, NCT04811560, NCT04988555) with explorative single-agent efficacy of ziftomenib reported in relapsed or refractory AML.Here, we selectively screened for synergistic treatment partners using a combinatorial drug screen and deciphered synergistic effects of ziftomenib on MLL-r and NPM1 mut AML.In order to characterize the single-drug treatment effects of ziftomenib, we first assessed its anti-proliferative activity in various MLL-r (MOLM13, MV411, OCI-AML2) and NPM1 mut (OCI-AML3) human AML cell lines.Similar to other menin inhibitors such as VTP-50469, we observed strong and dose-dependent inhibitory effects in all MLL-r and NPM1 mut AML at low nanomolar concentrations upon 7 days of treatment (half-maximal inhibitory concentration [IC 50 ] <25 nM; Figure 1A,B).HL60 and NB4 AML cells with-C