Modulación del metabolismo celular como blanco antitumoral en células de melanoma humano

Aggressive melanoma is still a highly live-threatening malignancy, being BRAF mutation its most frequent oncogenic driver, followed by NRAS mutation. Since metabolic rewiring has been involved in its progression and resistance, we hypothesized that the inhibition of key metabolic pathways could be a...

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Detalles Bibliográficos
Autor principal: Arbe, María Florencia
Otros Autores: Blank, Viviana
Formato: Tesis doctoral acceptedVersion
Lenguaje:Español
Publicado: Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica 2022
Materias:
Melanoma
Modulación metabólica
Resistencia a BRAFi
Metformina
Modulación de la vía de las pentosas fosfato
Bioenergetic modulation
BRAFi resistance
Metformin
Pentose phosphate pathway modulation
Ciencias de la vida
Acceso en línea:http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_7424
https://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_7424.dir/7424.PDF
Aporte de:
Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires
Descripción
Sumario:Aggressive melanoma is still a highly live-threatening malignancy, being BRAF mutation its most frequent oncogenic driver, followed by NRAS mutation. Since metabolic rewiring has been involved in its progression and resistance, we hypothesized that the inhibition of key metabolic pathways could be a promising therapeutic strategy. Thus, we studied the responses of eight human malignant melanoma cell lines, treated at different levels of key metabolic pathways, to address their vulnerability and to explore the behavioral relationships in terms of metabolic parameters and genetic backgrounds. We found that the order of responses was BRAFV600R?BRAFV600E>NRASQ61K. Therefore, we proposed that mutational status may not only be directly affecting the response to BRAF inhibitors (BRAFi) but also contributing to the highly metabolic plasticity of melanoma cells. In addition, the development of BRAFi resistance promoted OXPHOS dependence increasing the sensitivity to metformin. Finally, we found that the inhibition of the pentose phosphate pathway, in combination with metformin, highly decreased the viability of all melanoma cells, regardless their metabolic phenotype and their genetic background. These promising results encourage future preclinical studies to reveal its biological relevance.

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