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

MELINA GABRIELA CASTRO; CELIA NOEMÍ PEREZ; LUDMILA E CAMPOS; YAMILA I RODRIGUEZ; DARIO RAMIREZ; SERGIO ALVAREZ

Buenos Aires

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2016

Melanoma is the most aggressive form of skin cancer with a high mortality percentage. Half ofmelanoma patients display the BRAFV600E kinase mutation. Indeed, Food and Drugadministration (FDA) and ANMAT have approved the use of Vemurafenib and Dabrafenib (BRAFinhibitors) in melanoma patients. Unfortunately, patients develop resistance after a short periodof disease control, indicating that new targets are needed. In that regard, several evidencesconfirm that tumor microenvironment modulate proliferation, migration and acquired resistanceof cancer. Precisely, hypoxia is a remarkable feature of this picture that control cancer growth andprogression. Thus, the aim of this study was to elucidate how hypoxia influences the viability ofmelanoma cells. We used two melanoma cell lines: SKMel2 (BRAFWT) and Lu1205 (BRAFV600E).Surprisingly, hypoxia exerts a differential effect according to the culture conditions: whiledecreases viability of melanoma cells cultured in the presence of fetal bovine serum (FBS), itpartially protects of the reduced viability observed under serum deprivation conditions. To furtherinvestigate the effect in absence of serum, we used pharmacological inhibitors of differentsignaling pathways. Certainly, inhibition of NF-kB, PI3-K, MEK and hypoxia inducible factor 1 alpha(HIF1) pathways do not have an effect on viability of SKMel2 melanoma cells in hypoxia. On theother hand, HIF1 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 zonesof the tumor is not reduced by the deficiency of growth factors, but may be diminished byinhibition of BRAF with vemurafenib.