Radiotherapy (RT) in patients with
melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging
free radicals by
thiols, pigmentary machinery, or enhanced DNA repair. However,
radiotherapy has been utilized as adjuvant
therapy after the complete excision of primary
melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of
melanoma cells to
radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of
melanomas. In this study, we aimed to assess the potential benefit of adding RT to BRAF-mutated
melanoma cells under a combined p53 reactivation and MAPK inhibition in vitro and in a preclinical animal model. We found that the combination of BRAF inhibition (
vemurafenib, which completely shuts down the MAPK pathway), together with p53 reactivation (PRIMA-1Met) significantly enhanced the radiosensitivity of BRAF-mutant
melanoma cells. This was accompanied by an increase in both p53 expression and activity. Of note, we found that radiation alone markedly promoted both ERK and AKT phosphorylation, thus contributing to radioresistance. The combination of
vemurafenib and PRIMA-1Met caused the inactivation of both
MAPK kinase and PI3K/AKT pathways. Furthermore, when combined with
radiotherapy, it was able to significantly enhance
melanoma cell radiosensitivity. Interestingly, in nude mice bearing
melanoma xenografts, the latter triple combination had not only a synergistic effect on
tumor growth inhibition, but also a potent control on
tumor regrowth in all animals after finishing the triple combination
therapy. RT alone had only a weak effect. In conclusion, we provide a basis for a strategy that may overcome the radioresistance of BRAF-mutated
melanoma cells to
radiotherapy. Whether this will translate into a rational to use
radiotherapy in the curative setting in BRAF-mutated
melanoma patients deserves consideration.