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 capivaser

SUBMITTER: Cutano V 

PROVIDER: S-EPMC13631501 | biostudies-literature | 2026 Oct

REPOSITORIES: biostudies-literature