Abstract A023: Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer

Abstract

Abstract We previously described that the KDM5B histone H3 lysine 4 demethylase is amplified and overexpressed in luminal estrogen receptor positive breast cancer, and its activity is associated with resistance to endocrine therapies. We have found that the KDM5A paralog is specifically amplified and overexpressed in basal breast cancer, providing a novel therapeutic opportunity for an aggressive breast cancer subtype. To identify modulators of KDM5 inhibitor sensitivity in KDM5A-amplified basal breast cancer, we performed a genome wide CRISPR viability screen in a KDM5A-amplified basal breast cancer cell line. Our CRISPR screen results and follow up studies implicate Rho-GTPase signaling and the transcriptional repressor ZBTB7A as modulators of cellular response to KDM5 inhibition. We are currently investigating the underlying mechanisms for how these components alter sensitivity/resistance to KDM5 inhibition. Our results suggest potential therapeutic opportunities of inhibiting the KDM5 family of H3K4 demethylases in basal breast cancer. Citation Format: Benedetto DiCiaccio, Evangelia Papachristou, Malvina Papanastasiou, Andrew Reiter, Jason Carroll, Kornelia Polyak. Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A023.