NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2)

Abstract

Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most common events in human cancers. Several efforts have been made toward the identification of selective PI3K pathway inhibitors. However, the success of these molecules has been partially limited due to unexpected toxicities, the selection of potentially responsive patients, and intrinsic resistance to treatments. Metabolic alterations are intimately linked to drug resistance; altered metabolic pathways can help cancer cells adapt to continuous drug exposure and develop resistant phenotypes. Here we report the metabolic alterations underlying the non-small cell lung cancer (NSCLC) cell lines resistant to the usual PI3K-mTOR inhibitor BEZ235. In this study, we identified that an increased unsaturation degree of lipid species is associated with increased plasma membrane fluidity in cells with the resistant phenotype and that fatty acid desaturase FADS2 mediates the acquisition of chemoresistance. Therefore, new studies focused on reversing drug resistance based on membrane lipid modifications should consider the contribution of desaturase activity.

A novel gene signature related to fatty acid metabolism predicts prognosis, immune landscape, and drug sensitivity in early-stage lung squamous cell carcinoma

“…In ovarian cancer, inhibition of FADS2 directly downregulated GPX4 and the GSH/GSSG ratio, disrupted cellular/mitochondrial redox balance, and then leaded to iron-mediated lipid peroxidation and mitochondrial dysfunction in ascites-derived ovarian cancer cells ( 32 ). Another study indicated that FADS2 mediated resistance to PI3K/mTOR inhibitors in NSCLC ( 33 ). These findings suggest that the genes within this signature could potentially impact the prognosis of LUSC by regulating tumor lipid metabolism.…”