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

Abstract

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..