Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in acute myeloid leukaemia [CUT&Tag]

Understanding the molecular pathogenesis of MLL fusion oncoproteins (MLL-FP) has spawned epigenetic therapies that have improved clinical outcomes in this and other molecular subtypes of acute myeloid leukaemia (AML). Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate the oncogenic transcriptional program. Focussing on MLL-FP AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Consequently, combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Moreover, PF-9363 or genetic depletion reveals that KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.