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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.1927-1927
• Main Authors: Dyevoich, Allison, Harris, Koran, Miller, Lance, Langefeld, Carl D., Alli, Elizabeth
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-1927

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