NSCLC presents metabolic heterogeneity, and there is still some leeway for EGF stimuli in EGFR-mutated NSCLC

• Published in: Lung cancer (Amsterdam, Netherlands) Netherlands), 2023-08, Vol.182, p.107283-107283, Article 107283
• Main Authors: Mendes, Cindy, Lemos, Isabel, Francisco, Inês, Almodôvar, Teresa, Cunha, Fernando, Albuquerque, Cristina, Gonçalves, Luís G., Serpa, Jacinta
• Format: Article
• Language: English
• Subjects: Cancer metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell Line, Tumor; Epidermal Growth Factor - genetics; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; ErbB Receptors - genetics; ErbB Receptors - metabolism; Humans; Lung Neoplasms - drug therapy; Metabolic heterogeneity; Metabolic-directed therapy; Mutation; NSCLC; Proto-Oncogene Proteins p21(ras) - genetics
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2023.107283

•NSCLC cells and patient samples show heterogeneous metabolic profiles and may be associated to a particular genetic profile and histotypes.•EGF stimulus impacts the malignant features of EGFR mutated cell line PC-9 (EGFRdelE746-A750). Inhibiting EGFR with gefitinib promoted a decrease in glucose consumption and disturbed metabolic genes expression.•Inhibiting EGFR with gefitinib promoted a decrease in glucose consumption and disturbed metabolic genes expression.•Lactate exposure stimulates the expression of genes involved in lactate- and glucose-dependent pathways.•MCT1 and GLUT1 are positively correlated and upregulated in NSCLC metastatic patient samples. Metabolic remodeling is crucial in carcinogenesis and cancer progression. Oncogenic mutations may promote metabolic reprogramming in cancer cells to support their energy and biomass requirements. EGFR mutations are commonly found in non-small cell lung cancer (NSCLC) and may induce NSCLC metabolic rewiring. Whether EGFR-driven metabolic reprogramming triggers cell vulnerabilities with therapeutic potential remains unknown. The role of EGFR signaling activation by EGF was investigated using NSCLC cell lines with different EGFR and KRAS status: A549 (EGFR WT and KRAS c.34G > A), H292 (EGFR WT and KRAS WT) and PC-9 (EGFR exon 19 E746-A750 deletion and KRAS WT). The effect of EGF on NSCLC cell death and cell cycle was evaluated using flow cytometry, and cell migration was assessed through wound healing. EGFR, HER2, MCT1, and MCT4 expression was analyzed through immunofluorescence or western blotting. We explored the impact of glucose and lactate bioavailability on NSCLC cells' metabolic profile using nuclear magnetic resonance (NMR) spectroscopy. Moreover, the expression of several relevant metabolic genes in NSCLC cells or patient samples was determined by RT-qPCR. We showed that cell lines presented different metabolic profiles, and PC-9 cells were the most responsive to EGF stimulus, as they showed higher rates of cell proliferation and migration, together with altered metabolic behavior. By inhibiting EGFR with gefitinib, a decrease in glucose consumption was observed, which may be related to the fact that despite PC-9 harbor EGFR mutation, they still express the EGFR WT allele. The analysis of NSCLC patients' RNA showed a correlation between MCT1/MCT4 and GLUT1 expression in most cases, indicating that the metabolic information can serve as a reference in patients' follow-up. Together, this study show