p53 Family in Resistance to Targeted Therapy of Melanoma

Metastatic melanoma is one of the most aggressive tumors, with frequent mutations affecting components of the MAPK pathway, mainly protein kinase BRAF. Despite promising initial response to BRAF inhibitors, melanoma progresses due to development of resistance. In addition to frequent reactivation of MAPK or activation of PI3K/AKT signaling pathways, recently, the p53 pathway has been shown to contribute to acquired resistance to targeted MAPK inhibitor therapy. Canonical tumor suppressor p53 is inactivated in melanoma by diverse mechanisms. The TP53 gene and two other family members, TP63 and TP73, encode numerous protein isoforms that exhibit diverse functions during tumorigenesis. The p53 family isoforms can be produced by usage of alternative promoters and/or splicing on the C- and N-terminus. Various p53 family isoforms are expressed in melanoma cell lines and tumor samples, and several of them have already shown to have specific functions in melanoma, affecting proliferation, survival, metastatic potential, invasion, migration, and response to therapy. Of special interest are p53 family isoforms with increased expression and direct involvement in acquired resistance to MAPK inhibitors in melanoma cells, implying that modulating their expression or targeting their functional pathways could be a potential therapeutic strategy to overcome resistance to MAPK inhibitors in melanoma.

Automated summary

Metastatic melanoma, a highly aggressive tumor, is often characterized by mutations in the MAPK pathway, particularly in the protein kinase BRAF. However, resistance to BRAF inhibitors is a major obstacle in melanoma treatment, with the reactivation of MAPK or PI3K/AKT pathways and the involvement of the p53 pathway contributing to acquired resistance. In melanoma, the canonical tumor suppressor p53 is frequently inactivated through various mechanisms. The TP53 gene and its family members TP63 and TP73 encode multiple protein isoforms with diverse functions in tumorigenesis. Some p53 isoforms are expressed in melanoma cells and have been shown to play specific roles in proliferation, survival, metastasis, invasion, migration, and treatment response. Particularly, p53 isoforms involved in acquired resistance to MAPK inhibitors present potential therapeutic targets to overcome resistance in melanoma.