Abstract C022: Dual KAT6/7 inhibition delivers robust monotherapy anti-tumor activity in biomarker selected indications and disrupts emergence of drug-tolerant persister cell populations

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 challenging 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). Multiple lines of orthogonal evidence point to a “paralog” genetic relationship between these enzymes to support cancer cell autonomous survival in lineage-enriched CCLE subsets. Moreover, recent preclinical findings in pediatric and adult leukemia indicate the need to inhibit both KAT6 and KAT7 to deliver durable anti-tumor responses. These observations prompted evaluation of concomitant inhibition of KAT6 and KAT7 as a therapeutic approach in biomarker-defined solid cancers. Here, we report an equipotent KAT6/KAT7 dual inhibitor with high selectivity versus the structurally similar KAT family members KAT5/KAT8. We observed synergistic impact on cell viability and pharmacodynamic (PD) modulation of H3K23/H3K14 acetylation in biomarker positive breast, lung, and ovarian cancers with dual KAT6/7 inhibition versus selective inhibition of KAT6 or KAT7. Quantitative transcriptomic and epigenomic profiling of cancer cell responses to dual KAT6/7i revealed global inhibition of H3K23 and H3K14 acetylation as well as local suppression of H3K27ac-dependent enhancer elements at gene promoters controlling lineage specification, stemness, and WNT signaling. In vitro single cell RNA sequencing and protein expression analysis of ER+ PDX derived breast cancer cells indicated that dual KAT6/7 inhibition can overcome KAT6i associated adaptive drug resistance, downregulating drug tolerant persister cell states and metabolic adaptation. In vivo efficacy studies in biomarker positive breast and lung CDX models confirmed enhanced tumor growth inhibition and PD modulation for dual KAT6/7 versus selective KAT6 inhibition. Notably, dual KAT6/7 inhibition promoted durable and stable anti-tumor responses in multiple standard-of-care resistant and ESR1-mutant breast cancer PDXs that could not be achieved with KAT6 inhibition alone. In vivo bulk transcriptomics analysis of dual KAT6/7 treated PDX tumor samples highlighted disruption of lineage identity and metabolic rewiring. These observations indicate equipotent inhibition of KAT7 and KAT6A/B has the potential to deliver deep and durable anti-tumor activity in biomarker-selected patient populations. Citation Format: Manav Gupta, Scott R. Tyler, Nour Ghaddar, Pranav Gupta, Steven L. Spivak, Katelyn N. Lukas, Carl Schultz, Anjali Bisaria, Zabrisky Roland, Kelly S. Trego, Mason Appel, Parker Y. Jameson, Jacob Burch-Konda, Brittany Cruzan, Angelica Gonzalez-Sanchez, Monah Khalaj, Jay Prakash. Jain, Michael E . Dalziel, Julie Deichert, Sunjay Sethi, Ivan G. Shabalin, Rebeca Choy, Diana M. Munoz, Christian R. Frey, Peter Teriete, Josh Taygerly, Yuchen Bai, Richard Zang, Xin Linghu, Claire L. Neilan, Paul A. Barsanti, Michael A . White, Brian T. Jones. Dual KAT6/7 inhibition delivers robust monotherapy anti-tumor activity in biomarker selected indications and disrupts emergence of drug-tolerant persister cell populations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C022.