The impact of melanoma genetics on treatment response and resistance in clinical and experimental studies

Abstract

Recent attempts to characterize the melanoma mutational landscape using high-throughput sequencing technologies have identified new genes and pathways involved in the molecular pathogenesis of melanoma. Apart from mutated BRAF, NRAS, and KIT, a series of new recurrently mutated candidate genes with impact on signaling pathways have been identified such as NF1, PTEN, IDH1, RAC1, ARID2, and TP53. Under targeted treatment using BRAF and MEK1/2 inhibitors either alone or in combination, a majority of patients experience recurrences, which are due to different genetic mechanisms such as gene amplifications of BRAF or NRAS, MEK1/2 and PI3K mutations. In principle, resistance mechanisms converge on two signaling pathways, MAPK and PI3K-AKT-mTOR pathways. Resistance may be due to small subsets of resistant cells within a heterogeneous tumor mass not identified by sequencing of the bulk tumor. Future sequencing studies addressing tumor heterogeneity, e.g., by using single-cell sequencing technology, will most likely improve this situation. Gene expression patterns of metastatic lesions were also shown to predict treatment response, e.g., a MITF-low/NF-κB-high melanoma phenotype is resistant against classical targeted therapies. Finally, more recent treatment approaches using checkpoint inhibitors directed against PD-1 and CTLA-4 are very effective in melanoma and other tumor entities. Here, the mutational and neoantigen load of melanoma lesions may help to predict treatment response. Taken together, the new sequencing, molecular, and bioinformatic technologies exploiting the melanoma genome for treatment decisions have significantly improved our understanding of melanoma pathogenesis, treatment response, and resistance for either targeted treatment or immune checkpoint blockade.

Keywords: BRAF; Checkpoint blockade; Melanoma phenotype; NRAS; Resistance mechanisms.