Targeting the chromatin modifying enzyme, KDM5C, enhances AKT inhibition response in ER+ breast cancer.

The AKT inhibitor capivasertib has demonstrated clinical benefit in combination with the selective ER degrader fulvestrant in PIK3CA, PTEN and AKT-1 altered estrogen receptor positive breast cancer (ER+ BC). A genome-wide CRISPR screen was performed in PI3K-AKT pathway altered ER+ BC cells exploring modifiers of response to capivasertib which identified different resistance and sensitivity drivers. Loss of chromatin regulators including KDM5C and KAT6A increased sensitivity to capivasertib. Genetic knockout or pharmacological inhibition of KDM5C strongly enhanced the anti-proliferative effects of capivasertib monotherapy, as well as in combination with fulvestrant in treatment naïve and endocrine therapy or capivasertib resistant ER+ BC cell lines. RNA-seq 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 signalling. 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 suggests that chromatin regulators may have different functions following capivasertib treatment, with inhibition having potential to enhance sensitivity to capivasertib in PIK3CA, PTEN and AKT-1 altered ER+ BC cells.