1. Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.
- Author
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Gordon SJV, Perner F, MacPherson L, Wenge DV, Bourgeois W, Fennell K, Klaus T, Petrovic J, Horvath J, Cao J, Lapek J, Uryu S, White J, Lam EYN, Mu XJ, Chan YC, Gillespie A, Blyth B, 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, and Dawson MA
- Abstract
Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. 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 MLL-FP transcriptional program. Inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of 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 of KAT7 can also overcome acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy in MLL-FP leukaemia.
- Published
- 2024
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