Abstract 1181: Combined inhibition of KAT6 and menin reverses estrogen receptor-driven gene expression programs in breast cancer

Abstract The estrogen receptor (ER) is expressed in ∼70% of breast cancers where it functions as a critical transcription factor that regulates cell growth and tumor progression. Despite the clinical benefit of inhibiting ER, breast cancer remains the second leading cause of cancer-related death in women, with ∼50% of deaths resulting from ER+ tumors. While recurrent and metastatic ER+ tumors are typically resistant to endocrine therapies they continue to rely on ER signaling, suggesting that disruption of other chromatin associated complexes that mediate ER-driven gene expression may present an alternative therapeutic strategy. One chromatin modifier important in regulating ER function is the histone acetyltransferase KAT6A. KAT6A is amplified and/or overexpressed in ∼15% of ER+ tumors and a novel KAT6 inhibitor has entered clinical trials for metastatic breast cancer. However, as with most single agent therapies, many tumors responded only modestly to KAT6 inhibition. We hypothesized that the dual targeting of distinct chromatin complexes would enhance the effects of KAT6 inhibition, by altering chromatin state and transcriptional output. To that end we performed an epigenetic focused CRISPR-Cas9-based functional genetic screen to identify chromatin-associated proteins that augment the effects of KAT6 inhibition. CRISPR guides targeting MEN1 (encoding Menin) were among our top hits as sensitizers to treatment with the KAT6 inhibitor. We confirmed that co-treatment of KAT6 and Menin inhibitors had strong synergistic anti-proliferative effects in a panel of ER+ breast cancer cell lines, organoid models, and patient-derived xenografts. Mechanistically, our data revealed that KAT6A and Menin cooperatively regulate ER-driven gene expression and chromatin accessibility, both through direct effects on ESR1 expression as well as through effects at ER target genes. Specifically, we found that KAT6A and Menin-KMT2A complexes co-localized at promoters of ER target genes and treatment with KAT6 or Menin inhibitors displaced KAT6A and Menin/KMT2A, respectively. However, only the combination effectively displaced both complexes from chromatin and induced acute loss of RNA Pol2 binding specifically and selectively at ER-regulated genes. Importantly, the combination of KAT6 and Menin inhibition was effective in various models of endocrine resistance, including models with ESR1 mutations, NF1 loss, and FOXA1 mutations. Both KAT6 and Menin inhibitors have shown manageable toxicity profiles to date, underscoring that this combination therapy might represent a novel therapeutic approach for treatment resistant ER+ breast cancer. Citation Format: Sarah Naomi Olsen, Bryn Anderson, Charles Hatton, Myles Brown, Rinath Jeselsohn, Eneda Toska, Scott Armstrong. Combined inhibition of KAT6 and menin reverses estrogen receptor-driven gene expression programs in breast cancer [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 1181.