Abstract 4290: Long chain fatty acid elongase 6 is a novel therapeutic target for breast cancer

Abstract Cancer cells alter the quality of lipids to grow and survive. De novo synthesized fatty acids need to be elongated to provide numerous varieties to lipids. Despite the critical functions of lipid metabolism in cell function, how specific elongase contributes to tumor progression remains incompletely understood. In breast cancer (BRCA), retinoblastoma 1 (RB1) mutation or deletion is considered as one of the key factors promoting tumor progression. We previously reported that loss of RB1 transcriptionally upregulates the elongation of long chain fatty acid family member 6 (ELOVL6). We observed that BRCA cells with lower RB1 expression tend to show high ELOVL6 expression. ELOVL6 inhibition reduced cell proliferation in all subtypes of BRCA cells in vitro and in vivo. Moreover, RB1 loss sensitized these cells to undergo apoptosis following ELOVL6 depletion. These data indicate that ELOVL6 may have synthetic lethal relationship with RB1. We tried to elucidate the mechanism whereby ELOVL6 inhibition causes anti-tumor effects from a metabolic perspective. We noticed that ELOVL6 depletion reduced p-AKT levels in BRCA cells. Using a lipidomic approach, we observed that ELOVL6 depletion caused significant increase in the amount of intracellular ceramide and glycosphingolipids and decrease in sphingomyelin. Cell death associated with enhanced accumulation of ceramide was observed in cells in which both RB1 and ELOVL6 depletion. Inhibition of serine palmitoyltransferase 1 (SPTLC1) restored the p-AKT level and cell proliferation. These results suggest that ELOVL6 inhibition reduces p-AKT level by enhancing ceramide accumulation thereby suppressing cell proliferation. Taken together, our observations suggest that ELOVL6 is a promising therapeutic target in BRCA. Citation Format: Linxiang Gong, Susumu Kohno, Chiaki Takahashi. Long chain fatty acid elongase 6 is a novel therapeutic target for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4290.