MELANOMA CELLS WITH ACQUIRED RESISTANCE TO VEMURAFENIB HAVE DECREASED AUTOPHAGIC FLUX AND DISPLAY ENHANCED ABILITY TO TRANSFER RESISTANCE

FALCÓN CRISTIAN ROBERTO; PEREZ CELIA; MONS JOHINNA; CUELLO ORLANDI SERGIO FEDERICO; SANGIACOMO RUIZ MERCEDES L; FERNANDEZ MUÑOZ J; GUERRERO-GIMENEZ M; BENITO PAULA G.; COLOMBO MARÍA ISABEL; ZOPPINO F; ALVAREZ SERGIO

BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2023

0925-4439

Over the last years, the incidence of melanoma, the deadliest form of skin cancer, hasrisen significantly. Nearly half of the melanoma patients exhibit the BRAFV600Emutation. Although the use of BRAF and MEK inhibitors (BRAFi and MEKi) showed animpressive success rate in melanoma patients, durability of response remains an issuebecause tumor quickly becomes resistant. Here, we generated and characterizedLu1205 and A375 melanoma cells resistant to vemurafenib (BRAFi). Resistant cells(Lu1205R and A375R) exhibit higher IC50 (5-6 fold increase) and phospho-ERK levelsand 2-3 times reduced apoptosis than their sensitive parents (Lu1205S and A375S).Moreover, resistant cells are 2-3 times bigger, display a more elongated morphologyand have a modulation the migration capacity. Interestingly, pharmacological inhibitionof sphingosine kinases, that prevents sphingosine-1-phosphate production, reducesmigration of Lu1205R cells by 50%. In addition, although Lu1205R cells showedincreased basal levels of the autophagy markers LC3II and p62, they have decreasedautophagosome degradation and autophagy flux. Remarkably, expression of Rab27Aand Rab27B, which are involved in the release of extracellular vesicles aredramatically augmented in resistant cells (i.e. 5-7 fold increase). Indeed, conditionedmedia obtained from Lu1205R cells increased the resistance to vemurafenib ofsensitive cells. Hence, these results support that resistance to vemurafenib modulatesmigration and the autophagic flux and may be transferred to nearby sensitivemelanoma cells by factors that are released to the extracellular milieu by resistantcells.