Capivasertib is an AKT inhibitor approved for the treatment of HR+/HER2- advanced breast cancer with PIK3CA, PTEN, or AKT-1 alterations. To identify resistance mechanisms and combination opportunities, we performed CRISPR screens that revealed loss of chromatin regulators including KDM5C and KAT6A increased sensitivity to capivasertib. KDM5C inhibition increased cell stress, DNA damage, and apoptosis when combined with the AKT inhibitor, with the strongest effects in cancers harboring PIK3CA, PTEN, or AKT-1 alterations. These findings nominate KDM5C as a combination target to enhance AKT inhibition response in ER+ breast cancer.