Abstract 794: Inhibition of mitochondrial metabolism by a novel agent targeting RUNX2-DNA binding in breast cancer

Abstract

Abstract The RUNX2 transcription factor promotes breast cancer growth and metastasis through interactions with a variety of cofactors that activate or repress target genes. RUNX2 knockdown decreases expression levels of glycolytic genes such as LDHA, HK2 and GLUT-1, but upregulates PDHA1 mRNA level and enzymatic activity, which is consistent with lower glycolytic potential. Using a direct computer-assisted drug discovery (CADD) approach, we identified CADD522 as a small molecule that inhibits the RUNX2-DNA binding, transcriptional activity of RUNX2, and expression of RUNX2 target genes. We also observed that CADD522 inhibits breast cancer growth and metastasis using in vitro and in vivo tumor models. RUNX2-activated glucose utilization and GLUT-1 levels were also reduced by CADD522. New data also define CADD522 as a potential antitumor agent that downregulates the levels of metabolites in the TCA cycle and inhibits mitochondrial oxygen consumption rates. Our results support the observations that CADD522 could regulate cellular metabolism through modulation of both glycolytic metabolism and mitochondrial oxidative phosphorylation. To address the mechanisms by which CADD522 exerts its inhibitory effects on mitochondrial metabolism, we performed RNA-Sequencing analysis in breast cancer cells and identified several specific molecular signatures that determine cellular response to RUNX2 and CADD522. Further pathway changes in mitochondrial function as well as validation of differentially expressed genes that play critical roles in mitochondrial metabolism are under investigation. Citation Format: Myoung Sook Kim, Ramkishore Gernapudi, Yessenia C. Cedeno, Brian M. Polster, Geoffrey D. Girnun, Antonino Passaniti. Inhibition of mitochondrial metabolism by a novel agent targeting RUNX2-DNA binding in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 794.