Portal de Periódicos da CAPES

Abstract 1779 EGF-promoted metabolic and gene expression remodeling opens metabolism-based therapeutic opportunities in NSCLC

2024; Elsevier BV; Volume: 300; Issue: 3 Linguagem: Inglês

10.1016/j.jbc.2024.106462

1083-351X

Cindy Mendes, Isabel Lemos, Sara Granja, Fátima Baltazar, Luís G. Gonçalves, Vasco D. B. Bonifácio, Jacinta Serpa,

Cancer, Hypoxia, and Metabolism

Metabolic remodeling is critical in carcinogenesis and cancer progression. Oncogenic mutations drive metabolic reprogramming in cancer cells to support their energy and biomass needs. EGFR mutations in non-small cell lung cancer (NSCLC) are known to be associated with metabolic rewiring, whose impact on therapy response is unknown. The main objectives of this work were to explore the role of EGF and EGFR tyrosine kinase inhibitors (TKIs) in NSCLC metabolism and to validate SeChry@PUREG4-LA, targeting MCTs, as a therapeutical nanoformulation. NSCLC cell lines with different EGFR mutational profiles: H292 (EGFR WT) and PC-9 (EGFR exon 19 E746-A750 deletion) were exposed to glucose or lactate, with or without EGF supplementation. The effect of gefitinib, an EGFR-TKI, on metabolism was also assessed. We investigated how the availability of glucose and lactate influenced the metabolic characteristics of NSCLC cells using nuclear magnetic resonance (NMR) spectroscopy. The expression levels of several pertinent metabolic genes were assessed by RT-qPCR. SeChry@PUREG4-LA nanoparticles were tested as a putative therapeutical nanoformulation using annexin V-FITC and propidium iodide (PI) staining by flow cytometry. Additionally, in vivo testing was conducted through the chick chorioallantoic membrane (CAM) assay. We found that NSCLC cell lines react differently to EGF, being PC-9 the most responsive, with a great impact on cell metabolism, and a notorious rescue upon gefitinib exposure. The presence of lactate prompted an increase in the expression of genes related to pathways dependent on both lactate and glucose. Furthermore, the impact of gefitinib on these pathways varied depending on the specific cell line. MCT1 and/or MCT4 were pivotal in the adaptive process, and to take advantage of their expression, lactic acid functionalized dendrimeric nanoparticles loaded with selenium-chrysin (SeChry@PUREG4-LA) were tested as a therapy, in vitro and in vivo using a CAM assay. SeChry@PUREG4-LA significantly increased cell death in vitro and in vivo reduced tumor growth and tended to decrease angiogenesis. We also explored the potential of a double-drug approach using Sechry@PUREG4-LA and gefitinib and we found that it significantly potentiated cell death compared to the single treatments. This study highlights the diverse metabolic characteristics among NSCLC cell lines, potentially stemming from varying genetic profiles. This presents an opportunity to pinpoint and categorize patients who might respond favorably to therapies targeting metabolism. Finally, our results support SeChry@PUREG4-LA nanoparticles as a targeted strategy to improve NSCLC therapy. The institutions are funded by Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior through national funds (PTDC/MEDQUI/3542/2020). Cindy Mendes was funded by a FCT individual Ph.D. fellowship (2020.06956.BD).