This study evaluates and proposes an original drug combination not yet explored to break resistance to MAPK inhibitors in melanoma. Indeed, p53 is largely inactivated in melanoma and up-to-now very few studies are dedicated to reactivate this key pathway along with MAPK inhibition. Actually, one has been proposed and made its way to the clinic exploiting MDM2 inhibition (negative regulator of p53) with Nutlin-3.

In the present work, we evaluated a direct p53 activator, PRIMA-1^Met that is able to act whatever the mechanism of p53 deactivation, including TP53 mutations in combination with a clinically effective oncogenic BRAF inhibitor vemurafenib and showed very significant synergies both on intrinsic (innate) and acquired resistance to mutBRAF inhibitors. We also described an additional mechanism by which p53 can moderated the activation of PI3K/Akt pathway that is, beside the MAPK, the major resistance mechanism to mutBRAF inhibitors in melanoma.