Catalytic Inhibition of KAT6/KAT7 Enhances the Efficacy and Overcomes Primary and Acquired Resistance to Menin Inhibitors in MLL Leukemia
Year: 2025
Type: 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.
Source: Cancer Discovery
Authors: Shellaina J.V. Gordon, Florian Perner, Laura MacPherson, Katie A. Fennell, Daniela V. Wenge, Wallace Bourgeois, Tabea Klaus, Thomas Plenge, Anelya Murat, Jelena Petrovic, Jakub Horvath, Joan Q. Cao, John D. Lapek, Sean Uryu, Jeffrey R. White, Enid Y.N. Lam, Xinmeng Jasmine Mu, Yih-Chih Chan, Andrea Gillespie, Benjamin J. Blyth, Michelle A. Camerino, Ylva E. Bozikis, Henrietta Holze, Kathy Knezevic, Jesse Balic, Paul A. Stupple, Ian P. Street, Brendon J. Monahan, Shikhar Sharma, Elanor N. Wainwright, Dane Vassiliadis, Thomas A. Paul, Scott A. Armstrong, Mark A. Dawson
Institutions: The University of Melbourne, Peter MacCallum Cancer Centre, Boston Children's Hospital, Harvard University, Medizinische Hochschule Hannover, Dana-Farber Cancer Institute, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Pfizer (United States), University of California San Diego, Moores Cancer Center, Monash University, UNSW Sydney, Children's Cancer Institute Australia, Dana-Farber Brigham Cancer Center, The Royal Melbourne Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Pfizer, Celgene, Syndax Pharmaceuticals, Deutsche Forschungsgemeinschaft, Monash University, Else Kröner-Fresenius-Stiftung, Peter MacCallum Cancer Centre, Peter MacCallum Foundation, National Institutes of Health, National Health and Medical Research Council, Cancer Council Victoria, National Cancer Institute
Awards: G1570399396, Novel Therapeutic Strategies in Human Myeloid Leukemias, FOR 5659: TARGETMPN: Zielgerichtetes Vorgehen gegen KrankheitsPersistenz und Progression bei myeloproliferativen Neoplasien (MPN), G2019256308, G2020571142, Aberrante ChromatinKomplexe als Zielstrukturen in klonaler Hämatopoese und PräLeukämie., Improving outcomes for cancer patients by targeting the epigenome, G4841831832, G612573404, SPORE in Myeloid Malignancies, G7546166877, G7706152136, G8430490084
OpenAlex ID: W4411452307