Targeting the Chromatin-Modifying Enzyme, KDM5C, Enhances AKT Inhibition Response in ER+ Breast Cancer

Abstract The AKT inhibitor capivasertib has demonstrated clinical benefit in combination with the selective estrogen receptor (ER) degrader fulvestrant in PIK3CA-altered, PTEN-altered, and AKT-1–altered ER+ breast cancer. A genomewide CRISPR screen was performed in phosphoinositide (3)-kinase–AKT pathway–altered ER+ breast cancer cells exploring modifiers of response to capivasertib which identified different resistance and sensitivity drivers. Loss of chromatin regulators including lysine demethylase 5C (KDM5C) and KAT6A increased sensitivity to capivasertib. Genetic knockout (KO) or pharmacologic inhibition of KDM5C strongly enhanced the antiproliferative effects of capivasertib monotherapy, as well as in combination with fulvestrant in treatment-naïve and endocrine therapy–resistant or capivasertib-resistant ER+ breast cancer cell lines. RNA sequencing and epigenetic profiling revealed that combining capivasertib with KDM5C KO had a modest effect on gene transcription, with some effect on cell cycle–related genes and ER signaling. In contrast, combining capivasertib with fulvestrant enhanced the effects of fulvestrant on transcriptional output and promoter occupancy. Rather than influencing gene expression, loss of KDM5C combined with capivasertib increased cell stress, DNA damage, cell-cycle arrest, and cell death. Collectively, the data suggest that chromatin regulators may have different functions following capivasertib treatment, with inhibition having potential to enhance sensitivity to capivasertib in PIK3CA-altered, PTEN-altered, and AKT-1–altered ER+ breast cancer cells.