Abstract 442: Dual KAT6/7 inhibition disrupts epigenetic programs that promote tumor evolution and adaptive drug resistance

Abstract The formation of cancer and responsiveness to therapy is governed by a constantly evolving balance between somatic variation and dynamic epigenetic regulation. This evolution has been recognized as a significant obstacle confronting the development of durable cancer therapies. Thus, targeting epigenetic reprogramming in human cancers is a key focus for the design of new drugs to potentially deliver robust and durable anti-tumor activity. Lysine acetyltransferases (KATs) are a promising class of epigenetic targets that operate within interchangeable multi-subunit complexes to regulate cell cycle, pluripotency and lineage determination. Within this class, KAT6A and KAT7 have been recognized as mechanistically intertwined modulators of stem cell identity and lineage commitment through partially overlapping control of chromatin organization specified by histone H3 acetylation of lysine 23 (H3K23) and lysine 14 (H3K14). We noted multiple lines of orthogonal genetic evidence for a “paralog” relationship between these enzymes to support cancer cell autonomous survival in lineage-enriched subsets of the CCLE associated with predictive molecular features. These observations prompted evaluation of concomitant inhibition of KAT6A and KAT7 as a therapeutic approach in biomarker-defined patient populations. Here, we report an equipotent KAT6/KAT7 dual inhibitor with high selectivity versus the structurally similar KAT family members KAT5 and KAT8. We observed synergistic impact on cell viability and pharmacodynamic (PD) modulation of H3K23/H3K14 acetylation in biomarker positive breast, lung, and esophageal cancers with dual KAT6/7 inhibition versus selective inhibition of KAT6 or KAT7. In vitro transcriptomic evaluation of dual KAT6/7 drug effects in ER+ metastatic breast cancer models recapitulated convergent paralog behavior observed using genetic suppression with RNAi. Quantitative transcriptomic and epigenomic profiling of cancer cell responses to dual KAT6/7 inhibition confirmed downregulation of gene expression programs supporting lineage specification, stemness, and WNT signaling. In vivo efficacy studies in 8p11-amplified breast and lung xenografts confirmed enhanced tumor growth inhibition and PD modulation responses for dual KAT6/7 versus selective KAT6 inhibition. Notably, dual KAT6/7 inhibition also promoted improved durable and stable anti-tumor responses in endocrine therapy resistant and ESR1-mutant breast cancer patient derived xenografts that could not be achieved with selective KAT6 inhibition alone. Taken together, these observations support evaluation of dual KAT6/7 inhibition in biomarker-selected patient populations. Citation Format: Manav Gupta, Pranav Gupta, Scott R. Tyler, Nour Ghaddar, Steven L. Spivak, Zabrisky Roland, Katelyn N. Lukas, Ivan G. Shabalin, Jonathon S. Ryan, Carl Schultz, Daniel M. Walden, Santosh Keshipeddy, Muzaffar Alam, Daniel Severance, Anjali Bisaria, Kelly S. Tego, Parker Y. Jameson, Mason J. Appel, Brittany Cruzan, Jay Prakash Jain, Michael E. Dalziel, Sunjay Sethi, Rebeca Choy, Richard Zang, Xin Linghu, Yuchen Bai, Peter Teriete, Diana M. Muñoz, Christian R. Frey, Claire L. Neilan, Josh Taygerly, Jacob Burch-Konda, Paul A. Barsanti, Michael A. White, Brian T. Jones. Dual KAT6/7 inhibition disrupts epigenetic programs that promote tumor evolution and adaptive drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 442.