Metabolic reprogramming of sunitinib- and pazopanib-resistant renal cell carcinoma cells: a metabolomics approach
Background: Tyrosine kinase inhibitors (TKIs), such as sunitinib and pazopanib, changed the therapeutic landscape of metastatic renal cell carcinoma (RCC) [1,2]. However, TKIs resistance and disease progression within one year have been observed even in patients who initially respond to treatment . Hence, understanding the metabolic mechanisms associated with TKIs resistance is of utmost importance to reverse this issue and improve RCC treatment guidelines. Objective: This work applied a metabolomics approach to investigate the metabolic dysregulations underlying sunitinib and pazopanib resistance in a metastatic RCC cell line (Caki-1). Methods: Caki-1 cell line was continuously (6 months) exposed to increasing concentrations of sunitinib and pazopanib to induce resistance. Resistance was confirmed through the MTT assay by a 4.9- and 2.8-fold increase in the IC50 values of sunitinib and pazopanib-resistant cells compared with the parental cells, respectively. In the metabolomics assay, eight independent passages were considered for TKI-resistant and parental cells. Intracellular and extracellular metabolites were analyzed by proton nuclear magnetic resonance (1H NMR) spectroscopy. Statistical analysis comprised multivariate and univariate methods, and biological interpretation was performed through pathway analysis. Results: TKIs-resistant cells revealed a common reprogramming in the amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolisms. Sunitinib-resistant cells were also characterized by an enhanced cellular antioxidant capacity supported by a significant increase in the intracellular levels of glutathione and myo-inositol, and a significantly higher uptake of glutamine. On the other hand, pazopanib-resistant cells exhibited marked changes in several metabolites (e.g., glucose, lactate, pyruvate, acetate, succinate, fumarate) participating in energy metabolism. Conclusions: Our findings demonstrate for the first time a distinct pattern of metabolic alterations associated with sunitinib and pazopanib resistance in metastatic RCC cells. Targeting these dysregulations may constitute a promising strategy to restore cell sensitivity to treatment with these TKIs.
1. Escudier, B., Porta, C., Schmidinger, M., Rioux-Leclercq, N., Bex, A., Khoo, V., Grunwald, V., Gillessen, S., Horwich, A., ESMO Guidelines Committee. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up dagger. Ann. Oncol. 2019, 30, 706–720.
2. Motzer, R.J., Hutson, T.E., Cella, D., Reeves, J., Hawkins, R., Guo, J., Nathan, P., Staehler, M., de Souza, P., Merchan, J.R., et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med. 2013, 369, 722–731.
3. Buczek, M., Escudier, B., Bartnik, E., Szczylik, C., Czarnecka, A. Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: from the patient's bed to molecular mechanisms. Biochim Biophys Acta. 2014, 1845, 31-41.
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Copyright (c) 2023 E. Amaro, M. Carvalho, M. L. Bastos, P. Guedes de Pinho, J. Pinto
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