Clinical Implications of Acquired BRAF Inhibitors Resistance in Melanoma

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.

Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma

“…Over 50% of melanomas were found to be driven by BRAF V600E mutation, leading to promising developments in targeted therapy (i.e., BRAF inhibitors - vemurafenib, dabrafenib) over the past decade. Although specificity in genetic mutation and the targeted nature of the treatment provide short term resolution, cases of long-term relapse and recurrence remain prevalent ( Savoia et al., 2020 ). The involvement of non-genetic factors in conferring these abilities to tumors was identified based on drug-resistant subpopulations present in genetically identical cells ( Konieczkowski et al., 2014 ; Hartman et al., 2020 ).…”

Changes in the Transcriptome and Chromatin Landscape in BRAFi-Resistant Melanoma Cells

“…Several oncogenic BRAF-targeting inhibitors have been approved by the US FDA, including vemurafenib and dabrafenib, for the clinical treatment of metastatic melanoma (8,34,35). Although BRAFi therapy results in an impressive initial clinical response against BRAF-mutant metastatic melanoma, the durability of this response is limited by the rapid emergence of acquired BRAFi resistance, which often occurs within a few months of treatment initiation (36)(37)(38)(39). In the clinic, BRAFi therapy is often combined with other MAPK pathway inhibitors, such as MEKi, to obtain durable effects for the suppression of melanoma growth and the avoidance of drug resistance (6,10,12).…”

Molecular testing for melanocytic tumors: a practical update

“…BRAF inhibitors are effective only in BRAF mutated melanomas. They are not indicated in BRAF wild cases where they can cause paradoxical activation of MAPK pathway 105 . Therefore, for any melanoma in which BRAF‐inhibitor therapy is considered, BRAF gene mutation status needs to be evaluated.…”