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A deeper understanding of the metabolic mechanisms associated with TKI resistance is critical for refining therapeutic strategies. In this study, we established resistance to sunitinib and pazopanib by exposing a parental Caki-1 cell line to increasing concentrations of sunitinib and pazopanib. The intracellular and extracellular metabolome of sunitinib- and pazopanib-resistant mRCC cells were investigated using a nuclear magnetic resonance (NMR)-based metabolomics approach. Data analysis included multivariate and univariate methods, as well as pathway and network analyses. Distinct metabolic signatures in sunitinib- and pazopanib-resistant RCC cells were found for the first time in this study. A common metabolic reprogramming pattern was observed in amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolism. Sunitinib-resistant cells exhibited marked alterations in metabolites involved in antioxidant defence mechanisms, while pazopanib-resistant cells showed alterations in metabolites associated with energy pathways. Sunitinib-resistant RCC cells demonstrated an increased ability to proliferate, whereas pazopanib-resistant cells appeared to restructure their energy metabolism and undergo alterations in pathways associated with cell death. These findings provide potential targets for novel therapeutic strategies to overcome TKI resistance in mRCC through metabolic regulation.<\/jats:p>","DOI":"10.3390\/ijms25126328","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T10:43:42Z","timestamp":1717757022000},"page":"6328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Metabolomics Reveals Tyrosine Kinase Inhibitor Resistance-Associated Metabolic Events in Human Metastatic Renal Cancer Cells"],"prefix":"10.3390","volume":"25","author":[{"given":"Filipa","family":"Amaro","sequence":"first","affiliation":[{"name":"Associate Laboratory i4HB-Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal"},{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9884-4751","authenticated-orcid":false,"given":"M\u00e1rcia","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB-Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal"},{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"RISE-UFP, Health Research Network, Faculty of Health Sciences, University Fernando Pessoa, 4200-150 Porto, Portugal"}]},{"given":"Maria de Lourdes","family":"Bastos","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB-Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal"},{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7395-5700","authenticated-orcid":false,"given":"Paula","family":"Guedes de Pinho","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB-Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal"},{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9719-8364","authenticated-orcid":false,"given":"Joana","family":"Pinto","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB-Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal"},{"name":"UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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