P05.02 - Mitochondrial Metabolic Reprogramming of Melanoma Cells Exposed to BRAFV600E Inhibitor

Abstract

Metastatic melanoma deriving from the transformation of melanocytes is one of the most lethal cancers among young adults. About 50% of melanomas express the V600E mutation in the protein kinase BRAF that constitutively activate the MAPK pathways and results in dysregulated proliferation. The BRAFV600E mutation constitutes a potential target for new anti-melanoma treatments and in clinical trials, the BRAF inhibitors (eq vemurafenib) have demonstrated for the first time an improvement in both overall survival and progression free survival. But responses remain transitory and drug resistance occurs constantly and rapidly. Thus, there is an urgent need to develop new therapeutic approaches to achieve more-prolonged responses. Recent studies done using BRAFV600E cell lines have proved that the expression of the mutant kinase BRAFV600E is associated with metabolic modification mainly by the fact that inhibition of BRAFV600E in these cells causes a strong reduction of glucose uptake. However until these days any study has showed if there are other metabolic modifications in these cells. Using BRAFV600E melanoma cell lines and primary tumor samples, we have observed that vemurafenib induces an increase of mitochondrial oxygen consumption. Analysis of oxidative stress by flow cytometry shows an increase of reactive oxygen species (ROS) production both at mitochondrial and cytosolic level with alteration of glutathione pool and antioxidant enzyme activities. Finally, we have showed that vemurafenib-treated cells are more sensitive to oxidative stress insults caused by pro-oxidant molecules. Theses findings provide novel insights into the metabolic organization in vemurafenib-treated melanoma cells and open the door to innovative combinations that might increase vemurafenib efficiency. This work received a financial support from INSERM, UNIVERSITE DE LILLE II, Societe Francaise de Dermatologie, Ligue contre le Cancer (Comite de l’Aisne), Roche S.A.S, BMS-Groupe de Cancerologie Cutanee and a special financial support from the Association pour l’Etude des Anomalies Congenitales Neurodev of Pr. B. Poupard.