Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer (RNA-Seq)

KAT6A is a histone acetyltransferase that is emerging as a therapeutic target in cancer, including estrogen receptor positive (ER+) breast cancer. We performed CRISPR screens to identify the chromatin adaptor Menin as a regulator of KAT6A inhibitor response. Co-treatment with KAT6A/B and Menin inhibitors had synergistic anti-proliferative effects in ER+, but not ER-, breast cancer lines. Our data revealed that KAT6A and Menin cooperatively regulate ER-driven gene expression and chromatin accessibility via direct effects on ESR1 expression and at ER target genes. KAT6A and Menin co-localize at promoters of ESR1 and ER-driven genes and combined KAT6A/B and Menin inhibition selectively displaced RNA Pol II from chromatin at these loci. Combined KAT6A/B and Menin inhibition was effective in ER+ patient-derived organoids and in models of endocrine resistance. KAT6A/B and Menin inhibitors are currently in clinical trials and have shown manageable toxicity profiles, underscoring the potential therapeutic relevance for ER+ breast cancer.