Melanoma is known to be a radioresistant
cancer.
Melanoma radioresistance can be due to several factors such as pigmentation,
antioxidant defenses and high
Deoxyribonucleic acid (DNA) repair efficacy. However, irradiation induces intracellular translocation of RTKs, including cMet, which regulates response to DNA damage activating
proteins and promotes DNA repair. Accordingly, we hypothesized that co-targeting DNA repair (PARP-1) and relevant activated RTKs, c-Met in particular, may radiosensitize wild-type B-Raf Proto-Oncogene,
Serine/Threonine Kinase (WTBRAF)
melanomas where RTKs are often upregulated. Firstly, we found that PARP-1 is highly expressed in
melanoma cell lines. PARP-1 inhibition by
Olaparib or its KO mediates
melanoma cell sensitivity to
radiotherapy (RT). Similarly, specific inhibition of c-Met by
Crizotinib or its KO radiosensitizes the
melanoma cell lines. Mechanistically, we show that RT causes c-Met nuclear translocation to interact with PARP-1 promoting its activity. This can be reversed by c-Met inhibition. Accordingly, RT associated with the inhibition of both c-Met and PARP-1 resulted in a synergistic effect not only on
tumor growth inhibition but also on
tumor regrowth control in all animals following the stop of the treatment. We thus show that combining PARP and c-Met inhibition with RT appears a promising therapeutic approach in WTBRAF
melanoma.