Abstract 4499: KAT6i prifetrastat combines with PI3K pathway inhibitors to drive superior efficacy in preclinical models of PIK3CA mutated ER+ BC.

Abstract KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HATs) that acetylate histone H3K23 and regulate lineage-specific transcriptional programs. KAT6A/B activity is dysregulated in cancer, resulting in an oncogenic function for KAT6A/B in several tumor types, including in breast cancer. Prifetrastat is a first in class catalytic inhibitor of KAT6A and KAT6B with selectivity over other HAT enzymes. KAT6A/B inhibition results in downregulation of key pathways including estrogen signaling, cell cycle and MYC, resulting in anti-tumor activity in ER+ breast cancer. Here, we evaluate the activity of prifetrastat across a panel of breast cancer cell lines comprising different subtypes. Prifetrastat response was enriched in ER+, luminal subset of breast cancer cell lines with activity observed in both PIK3CA mutant and WT cells. Transcriptomic and chromatin accessibility analyses demonstrate that KAT6i treatment inhibits similar pathways in both PIK3CA WT and mutant cell lines. In vivo PDX studies also confirm the efficacy of prifetrastat in PIK3CA mutated models. Given the potential interplay between the mechanisms of action of KAT6i and PI3Kα inhibition in ER+ BC, we explored the potential of combining prifetrastat with PI3Kα inhibitors. In vitro drug combination studies demonstrate synergy between prifetrastat and several PI3Kα inhibitors including alpelisib and inavolisib as well as mutant selective PI3Kα inhibitors such as tersolisib across cell lines harboring PIK3CA helical or kinase domain mutations. Mechanistically, the combination of prifetrastat with PI3Kα inhibitors leads to further suppression of ER pathway genes and cell cycle pathways as compared to monotherapy activity. Finally, the triple combination of prifetrastat + Fulvesterant with PI3Kα inhibitors drives deeper tumor growth inhibition in PIK3CA mutant ER+ PDX models in vivo. Overall, we find that KAT6A/B inhibitors can effectively be combined with PI3Kα inhibitors and endocrine therapy to further drive efficacy in PIK3CA-mutant ER+BC indicating that the triplet combination could present a promising therapeutic option for this population. Citation Format: Kamakoti Prakash Bhat, Joan Q. Cao, Christopher Beldon Proffitt, Jelena Petrovic, Xinmeng Jasmine Mu, Kyle Spinler, Colin Ashton Flaveny, Thomas A. Paul, Joal Garrido Mayor, Heather Neumann, Shikhar Sharma. KAT6i prifetrastat combines with PI3K pathway inhibitors to drive superior efficacy in preclinical models of PIK3CA mutated ER+ BC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4499.