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

Gordon, SJV; Lapek, JD, Jr; Perner, F; Lam, EYN; MacPherson, L; Fennell, KA; Wenge, DV; Bourgeois, W; Klaus, T; Plenge, T; Murat, A; Petrovic, J; Horvath, J; Cao, JQ; Uryu, S; White, JR; Mu, XJ; Chan, YC; Gillespie, A; Blyth, BJ; Camerino, MA; Bozikis, YE; Holze, H; Knezevic, K; Balic, J; Stupple, PA; Street, IP; Monahan, BJ; Sharma, S; Wainwright, EN; Vassiliadis, D; Paul, TA; Armstrong, SA; Dawson, MA

Author(s): Gordon, SJV; Lapek, JD, Jr; Perner, F; Lam, EYN; MacPherson, L; Fennell, KA; Wenge, DV; Bourgeois, W; Klaus, T; Plenge, T; Murat, A; Petrovic, J; Horvath, J; Cao, JQ; Uryu, S; White, JR; Mu, XJ; Chan, YC; Gillespie, A; Blyth, BJ; Camerino, MA; Bozikis, YE; Holze, H; Knezevic, K; Balic, J; Stupple, PA; Street, IP; Monahan, BJ; Sharma, S; Wainwright, EN; Vassiliadis, D; Paul, TA; Armstrong, SA; Dawson, MA;
Details: Publication Year 2025-10-06,Volume 15,Issue #10,Page 2117-2138
Journal Title: Cancer Discovery
Publication Type: Research article
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 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.
Publisher: American Association for Cancer Research
Keywords: Humans; *Proto-Oncogene Proteins/antagonists & inhibitors/metabolism; *Leukemia, Myeloid, Acute/drug therapy/genetics/metabolism/pathology; *Drug Resistance, Neoplasm/drug effects; *Myeloid-Lymphoid Leukemia Protein/metabolism/genetics; Mice; Animals; *Histone Acetyltransferases/antagonists & inhibitors/metabolism/genetics; Histone-Lysine N-Methyltransferase/metabolism; Cell Line, Tumor; Xenograft Model Antitumor Assays; Oncogene Proteins, Fusion/genetics
Department(s): Laboratory Research; Haematology
Publisher's Version: https://doi.org/10.1158/2159-8290.Cd-24-1517
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-25 07:49:16

Last Modified: 2025-11-11 04:09:27