Abstract 1927: Evaluating molecular determinants of elesclomol sensitivity in breast cancer cells: An implication for metastatic properties

Abstract

Abstract Pre-clinical and clinical studies employing the experimental therapeutic elesclomol have produced contradictory findings. To better understand the mechanisms of response, we sought to identify molecular determinants that may predict elesclomol sensitivity. After stratifying human breast cell lines (n=8) into elesclomol-sensitive (n=4) and elesclomol-insensitive (n=4) groups, we first evaluated published predictors of elesclomol sensitivity, including lactate dehydrogenase (LDH) expression and various genomic aberrations. Though low levels of LDH have been reported to associate with elesclomol response in clinical samples, our data showed no statistically significant difference in LDHA (p=0.5) or LDHB (p=0.3) expression between elesclomol-sensitive and insensitive groups. Mining a human pan-cancer cell line dataset using the Genomics of Drug Sensitivity Database (GDSC) revealed an association between SMARC4A mutation and elesclomol sensitivity (MWW p=0.01) and between FLT3 chromosomal gain and elesclomol resistance (MWW p=0.00005), but the same investigation in a breast cancer cell line dataset produced no statistically significant genomic aberrations in association with elesclomol sensitivity. Indeed, none of our elesclomol-sensitive breast cell lines carried a SMARC4A mutation according to the Cancer Cell Line Encyclopedia, nor did they differentially express FLT3 relative to the elesclomol-insensitive lines as determined by expression profile data (p=1). Therefore, LDH expression and GDSC-defined genomic aberrations may not effectively predict elesclomol sensitivity in breast cancer. We then utilized transcriptomic data for each of our elesclomol-sensitive and insensitive cell lines to identify differentially-expressed genes (DEGs) and their functional annotations. A total of 456 DEGs (LFC>2, p<0.05) associated with elesclomol sensitivity based on an assessment of expression profiles within a single dataset using NCBI GEO2R. Interestingly, the DEGs tended to be enriched for molecules involved in cell adhesion (n=29, adj. p=0.02) according to an analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID). To better understand the relevance of these data, we considered that a loss of cell adhesion precedes invasion/metastasis, and discovered that our elesclomol-sensitive cell lines harbored a high invasive potential (n=2/2), whereas our insensitive lines harbored a low invasive potential (n=4/4). Therefore, an expression profile that lends to aberrant adhesion or high invasion potential may be used to predict sensitivity to elesclomol. Our findings not only introduce a relationship between an important hallmark of cancer, activating invasion and metastasis, and elesclomol sensitivity, but also rationalize future studies that explore elesclomol for the prevention of breast cancer metastasis. Citation Format: Allison Dyevoich, Koran Harris, Lance Miller, Carl D. Langefeld, Elizabeth Alli. Evaluating molecular determinants of elesclomol sensitivity in breast cancer cells: An implication for metastatic properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1927.