Catalytic Inhibition of KAT6/KAT7 Enhances the Efficacy and Overcomes Primary and Acquired Resistance to Menin Inhibitors in MLL Leukemia.

Targeting MYST acetyltransferases is an exciting therapeutic opportunity in acute myeloid leukemia (AML). In this study, we define the individual and combined contribution of KAT6A, KAT6B, and KAT7 in a range of AML models, showing that although KAT6A/B inhibition is efficacious in some preclinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with menin and the mixed lineage leukemia (MLL) complex and is colocalized at chromatin to coregulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (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. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription, and overcomes primary resistance to menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/nongenetic resistance to menin inhibition, providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML. SIGNIFICANCE: This study provides the molecular rationale for combined targeting of KAT6/7 and menin in MLL leukemia. It reveals that combination therapy results in a rapid and profound repression of the MLL transcriptional program leading to marked differentiation and loss of leukemia-initiating capacity, setting the platform for clinical translation.