Therapeutic effects of targeting RAS-ERK signaling in giant congenital melanocytic nevi

摘要

Most giant congenital melanocytic nevi (GCMN) exhibit an activating mutation in NRAS. Constitutive activation of the RAS-ERK signaling pathway induces proliferation in nevus cells and plays a pivotal role in melanoma development. In this study, we studied the efficacy of RAS-ERK pathway targeted therapy in GCMN. We isolated nevus cells from GCMN (GNCs) and compared the morphology of GNCs with normal melanocytes and the A375 melanoma cell line. Proliferation curves of GNCs and A375 cells were determined using Cell Counting Kit-8 assays. Cell cycle distribution was measured using flow cytometry. The RAS-ERK pathway inhibitors Vemurafenib and Trametinib, which are used in melanoma therapy, were applied. After inhibitor treatment, GNCs were analyzed for apoptosis and the protein expression of ERK, p-ERK, P38, p-P38 and P53. We found that compared with A375 cells, the cultured GNCs exhibited a higher G1 phase population and a lower proliferation rate. Both Vemurafenib and Trametinib treatment induced GNCs apoptosis in a dose-dependent manner, with Vemurafenib having a stronger effect. With inhibitor treatment, ERK activation was greatly suppressed, while the expression of p-P38 exhibited no obvious change. Vemurafenib treatment also increased the level of P53 protein in GNCs. These findings suggested that Vemurafenib treatment may be a potential therapeutic strategy for treatment of GCMN via targeting of the RAS-ERK pathway.