Targeting the c-MYC/ELOVL6 pathway alters cell membrane mechanics and enhances chemotherapeutic efficiency in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, with a survival rate of 12%. Therefore, finding new therapeutic strategies is a clinical emergency. Among the genetic alterations responsible of PDAC, the most common is the overexpression of the c-MYC oncogene, which acts as a key regulator of lipid metabolic pathways involved in proliferation, specifically in the synthesis and elongation of fatty acids. However, it is unknown the role c-MYC plays in the activity regulation of elongases of very-long-chain fatty acids (ELOVLs). In the present study, we investigate the role of the elongase ELOVL6 in c-MYC-induced cell transformation and its potential as a therapeutic target in PDAC. First, we demonstrated the direct regulation of ELOVLs expression by c-MYC in different PDAC cell lines. ELOVL6 interference in vitro by shRNAs and a chemical inhibitor (ELOVL6-IN-2) resulted in reduced proliferation and migration, fatty acid elongation and membrane thickness. Consequently, pinocytosis and membrane permeability were enhanced. Importantly, we showed a synergistic effect between paclitaxel and ELOVL6 interference. We validated in vivo that ELOVL6 interference (both by shRNAs and ELOVL6-IN-2) dramatically reduces tumor growth and enhances response to paclitaxel, increasing overall survival. Altogether, these results present ELOVL6 as a promising therapeutic target in PDAC treatment.