Melanoma cells with acquired resistance to vemurafenib have decreased autophagic flux and display enhanced ability to transfer resistance

Over the last years, the incidence of melanoma, the deadliest form of skin cancer, has risen significantly. Nearly half of the melanoma patients exhibit the BRAFV600E mutation. Although the use of BRAF and MEK inhibitors (BRAFi and MEKi) showed an impressive success rate in melanoma patients, durabi...

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Veröffentlicht in:Biochimica et biophysica acta. Molecular basis of disease 2023-10, Vol.1869 (7), p.166801-166801, Article 166801
Hauptverfasser: Pérez, Celia N., Falcón, Cristian R., Mons, Johinna Delgado, Orlandi, Federico Cuello, Sangiacomo, Mercedes, Fernandez-Muñoz, Juan M., Guerrero, Martín, Benito, Paula G., Colombo, María I., Zoppino, Felipe C.M.., Alvarez, Sergio E.
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Sprache:eng
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Zusammenfassung:Over the last years, the incidence of melanoma, the deadliest form of skin cancer, has risen significantly. Nearly half of the melanoma patients exhibit the BRAFV600E mutation. Although the use of BRAF and MEK inhibitors (BRAFi and MEKi) showed an impressive success rate in melanoma patients, durability of response remains an issue because tumor quickly becomes resistant. Here, we generated and characterized Lu1205 and A375 melanoma cells resistant to vemurafenib (BRAFi). Resistant cells (Lu1205R and A375R) exhibit higher IC50 (5–6 fold increase) and phospho-ERK levels and 2–3 times reduced apoptosis than their sensitive parents (Lu1205S and A375S). Moreover, resistant cells are 2–3 times bigger, display a more elongated morphology and have a modulation of migration capacity. Interestingly, pharmacological inhibition of sphingosine kinases, that prevents sphingosine-1-phosphate production, reduces migration of Lu1205R cells by 50 %. In addition, although Lu1205R cells showed increased basal levels of the autophagy markers LC3II and p62, they have decreased autophagosome degradation and autophagy flux. Remarkably, expression of Rab27A and Rab27B, which are involved in the release of extracellular vesicles are dramatically augmented in resistant cells (i.e. 5–7 fold increase). Indeed, conditioned media obtained from Lu1205R cells increased the resistance to vemurafenib of sensitive cells. Hence, these results support that resistance to vemurafenib modulates migration and the autophagic flux and may be transferred to nearby sensitive melanoma cells by factors that are released to the extracellular milieu by resistant cells. •Apoptosis is reduced in melanoma cells resistant to vemurafenib.•Resistance to vemurafenib increases the size and modulates migration of melanoma cells.•Autophagic flux is decreased in resistant cells.•Resistant cells are able to transfer the resistance to sensitive cells.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2023.166801