Abstract
Understanding the role of mitogen-activated protein kinase (MAPK) pathway-activating mutations in the development and progression of melanoma and their possible use as therapeutic targets has substantially changed the management of this neoplasm, which, until a few years ago, was burdened by severe mortality. However, the presence of numerous intrinsic and extrinsic mechanisms of resistance to BRAF inhibitors compromises the treatment responses’ effectiveness and durability. The strategy of overcoming these resistances by combination therapy has proved successful, with the additional benefit of reducing side effects derived from paradoxical activation of the MAPK pathway. Furthermore, the use of other highly specific inhibitors, intermittent dosing schedules and the association of combination therapy with immune checkpoint inhibitors are promising new therapeutic strategies. However, numerous issues related to dose, tolerability and administration sequence still need to be clarified, as is to be expected from currently ongoing trials. In this review, we describe the clinical results of using BRAF inhibitors in advanced melanoma, with a keen interest in strategies aimed at overcoming resistance.
Highlights
Melanoma is the twentieth most common cancer worldwide, with an incidence that has progressively increased over time as a consequence of lifestyles that accentuate photo-induced skin damage [1,2]
We describe the clinical results of using BRAF inhibitors in advanced melanoma, with a keen interest in strategies aimed at overcoming resistance
An immune-mediated mechanism of resistance has been hypothesized; despite the initial favorable effects on the tumor microenvironment exerted by BRAF inhibitors (BRAFi) and MEKi, low levels of CD8+ tumor-infiltrating T cells were observed in patients who rapidly progressed under targeted therapy [24], together with an increased expression of the immune inhibitory molecule programmed death-ligand progressive disease (PD)-L1 [25]
Summary
Melanoma is the twentieth most common cancer worldwide, with an incidence that has progressively increased over time as a consequence of lifestyles that accentuate photo-induced skin damage [1,2]. The landscape of possible therapeutic options for the treatment of advanced disease has been substantially modified by target therapies and by immunological checkpoint inhibitors [3]. Despite the amazing results obtained with first-generation kinase inhibitors in terms of response rate, the average duration of this response was short due to the onset of resistance to treatment. Combination therapy with BRAF/MEK inhibitors proved to be an excellent way to overcome the resistance mechanisms, such as the recent development of highly specific Extracellular Signal-Regulated Kinase (ERK) inhibitors [4]. Other possible strategies, including the combination of BRAF inhibitors (BRAFi) with immunotherapy, sequencing approaches and rechallenge or retreatment should be considered. The main clinical implications of BRAFi resistance will be analyzed, along with possible overcoming strategies
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