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NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2)
Marika Colombo1, Federico Passarelli1, Paola A Corsetto2
1Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
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.
Insights
Cancer cells resistant to PI3K-mTOR inhibitors show altered lipid metabolism. Fatty acid desaturase FADS2 activity increases membrane fluidity, mediating chemoresistance in non-small cell lung cancer.
Area of Science:
- Oncology
- Cancer Biology
- Metabolic Pathways
Background:
- Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway is a common driver in human cancers.
- Targeted PI3K inhibitors face challenges including toxicity, patient selection, and intrinsic drug resistance.
- Metabolic alterations are increasingly recognized as key contributors to cancer drug resistance.
Purpose of the Study:
- To investigate the metabolic alterations underlying resistance to the PI3K-mTOR inhibitor BEZ235 in non-small cell lung cancer (NSCLC).
- To identify specific metabolic pathways and molecular mechanisms that confer chemoresistance.
Main Methods:
- Utilized NSCLC cell lines with acquired resistance to BEZ235.
- Analyzed lipid species and plasma membrane properties in resistant versus sensitive cells.
- Investigated the role of fatty acid desaturase 2 (FADS2) in mediating resistance.
Main Results:
- Resistant NSCLC cells exhibited an increased degree of unsaturation in lipid species.
- This lipid unsaturation correlated with increased plasma membrane fluidity.
- FADS2 was identified as a key mediator responsible for the acquisition of chemoresistance.
Conclusions:
- Altered lipid metabolism, specifically increased membrane fluidity via FADS2 activity, is a critical mechanism of resistance to PI3K-mTOR inhibitors in NSCLC.
- Targeting desaturase activity and membrane lipid modifications presents a potential strategy to overcome chemoresistance.
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