Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?

Abstract

Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.

Keywords: DNA methylation; RASSF1A; melanoma; resistance; targeted therapy; tumour suppressor.

Figure 1

Schematic representation of the three subtypes of resistance mechanism against targeted therapy in melanoma: intrinsic, adaptive, and acquired. The main pathways and mutations accounting for each subtype are displayed.

Figure 2

Schematic representation of the molecular mechanisms conferring resistance to BRAFi-targeted therapy (upper panel) and RASSF1A-mediated regulation of associated signalling processes (lower panel). Letters a to f in the upper panel represent the potential impact of RASSF1A on counteracting BRAFi resistance mechanism. Subfigures a to f from lower panel show the different biochemical mechanism regulated by RASSF1A referred to in the upper panel. (Created with BioRender.com).