VEMURAFENIB REVERTS HYPOXIA-INDUCED INCREASE IN CELL VIABILITY OF BRAFV600E MELANOMA CELLS

CASTRO MG; PEREZ CN; CAMPOS LE; RODRIGUEZ YI; RAMIREZ DC; ALVAREZ SE

Mar del Plata

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC), LXIV REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA (SAI) XLVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE FARMACOLOGÍA EXPERIMENTAL (SAFE); 2016

SAIC, SAI y SAFE

Melanoma is the most aggressive form of skin cancer with a high mortality percentage. Half of melanoma patients display the BRAFV600E kinase mutation. Indeed, Food and Drug administration (FDA) and ANMAT have approved the use of Vemurafenib and Dabrafenib (BRAF inhibitors) in melanoma patients. Unfortunately, patients develop resistance after a short period of disease control, indicating that new targets are needed. In that regard, several evidences confirm that tumor microenvironment modulate proliferation, migration and acquired resistance of cancer. Precisely, hypoxia is a remarkable feature of this picture that control cancer growth and progression. Thus, the aim of this study was to elucidate how hypoxia influences the viability of melanoma cells. We used two melanoma cell lines: SKMel2 (BRAFWT) and Lu1205 (BRAFV600E). Surprisingly, hypoxia exerts a differential effect according to the culture conditions: while decreases viability of melanoma cells cultured in the presence of fetal bovine serum (FBS), it partially protects of the reduced viability observed under serum deprivation conditions. To further investigate the effect in absence of serum, we used pharmacological inhibitors of different signaling pathways. Certainly, inhibition of NF-kB, PI3-K, MEK and hypoxia inducible factor 1 alpha (HIF1alpha) pathways do not have an effect on viability of SKMel2 melanoma cells in hypoxia. On the other hand, HIF1alpha is crucial for the hypoxia-induced protection of Lu1205 melanoma cell viability. Interestingly, inhibition of BRAF with vemurafenib also reverts the effect of hypoxia in Lu1205melanoma cells. Altogether, these results suggest that viability of cancer cells in the hypoxic zones of the tumor is not reduced by the deficiency of growth factors, but may be diminished by inhibition of BRAF with vemurafenib.