Overcoming Menin inhibitor resistance in AML cells with combinations including BET proteins and dual BRG1/BRM inhibitor - PubMed
4 hours ago
- #AML
- #Menin inhibitor resistance
- #targeted therapy
- Menin inhibitors (MI) disrupt Menin-MLL1 binding, reducing HOXA9 and MEIS1 in AML with NPM1 mutations or MLL1 rearrangements.
- MI resistance develops in AML cells, leading to relapse, without Menin mutations but with altered epigenome, transcriptome, and proteome.
- CRISPR screen identified druggable targets like BRD4, SMARCA4, and CREBBP to overcome MI resistance.
- Combining MI with BRG1/BRM inhibitor FHD-286 or BET inhibitor OTX015 synergistically kills resistant AML cells in vitro.
- In vivo, combinations of revumenib (SNDX-5613) with FHD-286 or OTX015 with FHD-286 reduced AML burden and improved survival in xenograft models.
- These combinations show promise for overcoming MI resistance in MLL1-rearranged or NPM1-mutant AML.