Everolimus selectively targets vemurafenib resistant BRAF melanoma cells adapted to low pH

Vemurafenib, a BRAF inhibitor, elicits in ∼80 % of BRAFV600E-mutant melanoma patients a transient anti-tumor response which precedes the emergence of resistance. We tested whether an acidic tumor microenvironment may favor a BRAF inhibitor resistance. A375M6 BRAFV600E melanoma cells, either exposed for a short period or chronically adapted to an acidic medium, showed traits compatible with an epithelial-mesenchymal transition, reduced proliferation and high resistance to apoptosis. Both types of acidic cells treated with vemurafenib did not change their proliferation, distribution in cell cycle and level of p-AKT, in contrast to cells grown at standard pH, which showed reduced proliferation, cell cycle arrest and ERK/AKT inhibition.

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