Abstract 1691: p300 catalytic inhibition selectively targets IRF4 oncogenic activity in multiple myeloma

Abstract Multiple myeloma (MM), an incurable plasma cell malignancy, is addicted to oncogenic transcription factor (TF) IRF4 signaling. Lineage TFs like IRF4 are difficult to drug but represent high value oncology targets owing to the depth and context selectivity of their genetic dependency. Using a transcription regulatory network (TRN) based approach to integrate a high dimensional multi-platform dataset, we defined the key regulatory activity of IRF4 and its druggable co-factors. This unbiased analysis identified p300 lysine acetyl transferase (KAT) function as the nearest selective neighbor for therapeutic intervention, with more potent and selective effects than historically observed with p300/CBP bromodomain inhibitors. To further probe this biology, we developed a highly selective inhibitor of the KAT domain of p300 and its close homolog CBP. p300 KAT inhibition led to selective downregulation of IRF4 at the mRNA and protein level as well as reduction in acetylation at highly specific sites co-localized with IRF4, in contrast to more general agents like BET inhibitors. Gene expression reduction was most pronounced at IRF4/p300 co-bound genes, in particular IRF4 itself and MYC. IRF4 and p300 also directly bind to each other and other key MM nodes regulating them at the chromatin, mRNA, and protein levels. p300 KAT inhibition exhibits strong antiproliferative activity across in vitro MM models regardless of cytogenetics or resistance to other therapies. Moreover, this relationship is mediated by the KAT domain and not its acetyl-lysine recognizing bromodomain. Comparative pharmacology studies found that a p300 KAT inhibitor downregulated the IRF4 TRN and induced apoptosis in MM cells more effectively than existing standard of care agents, including IMiDs and glucocorticoid receptor agonists, or p300/CBP bromodomain inhibitors. Combinations of a p300 KAT inhibitor with clinically active molecules such as IMiDs and glucocorticoid agonists showed synergistic impacts on reducing key MM TFs and cell line viability. Ex vivo treatment of primary patient samples demonstrated broad anti-proliferative activity with loss of IRF4 and induction of apoptosis in relapsed-refractory MM patient samples, independent of prior lines of therapy. Importantly, the induction of MM cell apoptosis occurs in the milieu of CD138 negative bone marrow stromal cells while also sparing them from toxicity, supporting a potential therapeutic index. Finally, p300 KAT inhibition demonstrated activity in in vivo MM models with robust tumor growth inhibition at tolerated doses and exposures correlated to reduced p300-dependent substrate acetylation. IRF4 dependency is a hallmark of MM that has been challenging to target with existing therapies, motivating further development of p300 KAT targeting therapeutics. Citation Format: Michael R. McKeown, Giulia Giorgetti, Walter F. Lenoir, Marek J. Kobylarz, Tamara D. Hopkins, Wayne L. Glore, Michelle G. Shum, Yare Calderon, Kameron R. Mori, Hua Gao, Luis A. Carvajal, Nikolaus D. Obholzer, Benjamin W. Trotter, Christopher D. Dinsmore, Nikhil C. Munshi, Peter B. Rahl, Mariateresa Fulciniti, Charles Y. Lin. p300 catalytic inhibition selectively targets IRF4 oncogenic activity in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1691.