Abstract 3007: The epigenetic regulators KDM5C and KAT6A influence AKT inhibitor response in ER positive breast cancer

Abstract Breast cancer is one of the most common cancers worldwide, and around 80% of breast cancers are oestrogen receptor positive (ER+ BC). For patients with ER+ advanced BC with one or more PIK3CA/AKT1/PTEN tumor alterations, capivasertib (AKT inhibitor) in combination with fulvestrant (selective oestrogen receptor (ER) degrader) is a recommended treatment. An innate PI3K/AKT pathway inhibitor resistance can occur in patients with ER+ BC, limiting their efficacy. Therefore, novel therapeutic strategies are needed to increase sensitivity to treatments in patients with ER+ BC. With this aim, from CRISPR-based sensitization screens in ER+ BC cells, we have found that the effectiveness of the AKT inhibitor capivasertib is improved by targeting the epigenetic regulators, KDM5C (lysine demethylase 5C) or KAT6A (lysine acetyltransferase 6A). Knockout (KO) of KDM5C or KAT6A strongly enhances the response to capivasertib monotherapy and its treatment in combination with fulvestrant in PIK3CA-mut and PTEN-null ER+ BC cells, as well as re-sensitizes capivasertib-resistant ER+ BC cells. Importantly, the effects of the genetic KO were recapitulated with a pan-KDM5 inhibitor and a selective KAT6A/B inhibitor in combination with capivasertib in ER+BC cells, suggesting that combination therapies, consisting of capivasertib with KDM5 or KAT6A inhibitors, could be beneficial in patients. Moreover, transcriptomic analysis and chromatin profiling techniques show that both KDM5C and KAT6A KO downregulate expression and alter chromatic accessibility of a subset of ER-target genes and this phenotype is enhanced in combination with capivasertib, suggesting that targeting KDM5C or KAT6A sensitizes cells to AKTi through a novel epigenetic regulation of ER-signaling. Also, this study reports for the first time a landscape of epigenetic differences upon capivasertib monotherapy treatment and in combination with fulvestrant in ER+BC cells, revealing changes in chromatin accessibility as a consequence of treatment with AKTi and the ER degrader. This suggests that epigenetic remodelling can lead to resistance to capivasertib and fulvestrant therapy in cancer cells. In summary, this findings identified and validated KDM5C and KAT6A as novel epigenetic targets, the inhibition of which enhances efficacy of AKTi in PI3K pathway mutated ER+ breast cancer. Inhibitors of KDM5C and KAT6A may be potential combination partners for capivasertib in ER+ breast cancer. Citation Format: Valentina Cutano, Shanade Dunn, Lorna Hopcroft, Eleanor M. Wigmore, Lambert Montava Garriga, Sungmi Park-Chouinard, Wu Qing, Lee Hyung Joo, Cath Eberlein, Michele Chirichella, Daniel Barrell, Toby Gurran, Omid Tavana, Neeraj Aryal, Jerome T. Mettetal, Huayang Liu, Ho Man Chan, Susan E. Critchlow, Ultan McDermott, Simon T. Barry. The epigenetic regulators KDM5C and KAT6A influence AKT inhibitor response in ER positive 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 3007.