An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells

ABSTRACTThe ingrained capacity of melanomacells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAFV600E. Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenibresistance. However, how this vesicular trafficking pathway supports Vemurafenib resistanceremains unclear. Here, using isogenic human and murine melanomacell lines of Vemurafenib-resistant and patient-derived melanomacells with primary resistance to the BRAFV600E inhibitor, we found that the enhanced migration and invasion of the resistant melanomacells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP. Extracellular ATP (eATP) was instrumental for the invasive phenotype and the expansion of a subset of Vemurafenib-resistant melanomacells. Compromising the heightened autophagy in these...