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

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 PI3Kalpha inhibition in ER+ BC, we explored the potential of combining prifetrastat with PI3Kalpha inhibitors. In vitro drug combination studies demonstrate synergy between prifetrastat and several PI3Kalpha inhibitors including alpelisib and inavolisib as well as mutant selective PI3Kalpha inhibitors such as tersolisib across cell lines harboring PIK3CA helical or kinase domain mutations. Mechanistically, the combination of prifetrastat with PI3Kalpha 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 PI3Kalpha 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 PI3Kalpha 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.