Abstract
BackgroundNon-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations are successfully treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, resistance to treatment inevitably occurs. Given lipid metabolic reprogramming is widely known as a hallmark of cancer and intimately linked with EGFR-stimulated cancer growth. Activation of EGFR signal pathway increased monounsaturated fatty acids (MUFA) and lipid metabolism key enzyme Stearoyl-CoA Desaturase 1 (SCD1) expression. However the correlation between EGFR-TKI resistance and lipid metabolism remains to be determined.MethodsIn this study the differences in lipid synthesis between paired TKI-sensitive and TKI-resistant patient tissues and NSCLC cell lines were explored. Oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) was used to simulate a high lipid metabolic environment and detected the affection on the cytotoxic effect of TKIs (Gefitinib and osimertinib) in cell lines with EGFR-activating mutations. (20S)-Protopanaxatriol (g-PPT), an aglycone of ginsenosides, has been reported to be an effective lipid metabolism inhibitor, was used to inhibit lipid metabolism. Additionally, synergism in cytotoxic effects and signal pathway activation were evaluated using CCK-8 assays, Western blotting, flow cytometry, Edu assays, plate clone formation assays and immunofluorescence. Furthermore, two xenograft mouse models were used to verify the in vitro results.ResultsGefitinib-resistant cells have higher lipid droplet content and SCD1 expression than Gefitinib-sensitive cells in both NSCLC cell lines and patient tissues. Additionally oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) abrogates the cytotoxic effect of both Gefitinib and osimertinib in cell lines with EGFR-activating mutations. As a reported effective lipid metabolism inhibitor, g-PPT significantly inhibited the expression of SCD1 in lung adenocarcinoma cells, and then down-regulated the content of intracellular lipid droplets. Combined treatment with Gefitinib and g-PPT reverses the resistance to Gefitinib and inhibits the activation of p-EGFR and the downstream signaling pathways.ConclusionsOur findings uncover a link between lipid metabolic reprogramming and EGFR-TKI resistance, confirmed that combination target both EGFR and abnormal lipid metabolism maybe a promising therapy for EGFR-TKI resistance and highlighting the possibility of monitoring lipid accumulation in tumors for predicting drug resistance.
Highlights
Lung cancer is one of the most predominant and fatal cancers worldwide, and non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases [1]
As a reported effective lipid metabolism inhibitor, g-PPT significantly inhibited the expression of Stearoyl-CoA Desaturase 1 (SCD1) in lung adenocarcinoma cells, and down-regulated the content of intracellular lipid droplets
Our findings uncover a link between lipid metabolic reprogramming and epidermal growth factor receptor (EGFR)-TKI resistance, confirmed that combination target both EGFR and abnormal lipid metabolism maybe a promising therapy for EGFR-TKI resistance and highlighting the possibility of monitoring lipid accumulation in tumors for predicting drug resistance
Summary
Lung cancer is one of the most predominant and fatal cancers worldwide, and non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases [1]. An important milestone in the treatment of NSCLC was the discovery of epidermal growth factor receptor (EGFR)-activating mutations as an effective therapeutic target and the successful development of third-generation EGFR tyrosine kinase inhibitors (EGFRTKIs; Gefitinib, erlotinib, afatinib, and osimertinib). The reprogramming of lipid metabolic pathways in cancer cells has been shown to play an important role in supporting cancer cell proliferation and survival [6, 7]. Non-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations are successfully treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs); resistance to treatment inevitably occurs. Given lipid metabolic reprogramming is widely known as a hallmark of cancer and intimately linked with EGFR-stimulated cancer growth. The correlation between EGFR-TKI resistance and lipid metabolism remains to be determined
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.