Abstract
In BRAFV600mut metastatic melanoma, the combination of BRAF and MEK inhibitors (BRAFi, MEKi) has undergone multiple resistance mechanisms, limiting its clinical benefit and resulting in the need for response predicting biomarkers. Based on phase III clinical trial data, several studies have previously explored baseline genomic features associated with response to BRAFi + MEKi. Using a targeted approach that combines the examination of mRNA expression and DNA alterations in a subset of genes, we performed an analysis of baseline genomic alterations involved in MAPK inhibitors’ resistance in a real-life cohort of BRAFV600mut metastatic melanoma patients. Twenty-seven patients were included in this retrospective study, and tumor samples were analyzed when the BRAFi + MEKi therapy was initiated. The clinical characteristics of our cohort were consistent with previously published studies. The BRAFi + MEKi treatment was initiated in seven patients as a following-line treatment, and had a specific transcriptomic profile exhibiting 14 genes with lower mRNA expression. However, DNA alterations in CCND1, RB1, and MET were only observed in patients who received BRAFi + MEKi as the first-line treatment. Furthermore, KIT mRNA expression was significantly higher in patients showing clinical benefit from the combined therapy, emphasizing the tumor-suppressor role of KIT already described within the context of BRAF-mutant melanoma.
Highlights
BRAFV600-mutated (BRAFV600mut ) lesions are currently described in approximately 50% of patients with metastatic melanoma, and are known to constitutively activate the MAPK pathway [1,2]
Twenty-seven (n = 27) BRAFV600mut metastatic melanoma patients were included in this study, and baseline tumor samples were collected
We present an exploratory analysis of a cohort of BRAFV600mut metastatic melanoma patients initiating BRAF inhibitor (BRAFi) + MEKi treatment followed in a real-world setting
Summary
BRAFV600-mutated (BRAFV600mut ) lesions are currently described in approximately 50% of patients with metastatic melanoma, and are known to constitutively activate the MAPK (mitogen-activated protein kinase) pathway [1,2]. In the last few years, therapies targeting this pathway, such as those involving a BRAF inhibitor (BRAFi), have greatly improved the clinical outcome of BRAFV600mut metastatic melanoma [3,4,5,6,7,8]. Frequent events leading to this reactivation suggest events such as MAP2K1, MAP2K2, or NRAS mutations, BRAF amplifications, or NF1 inactivation Other resistance mechanisms, such as PI3K/AKT pathway activation via PTEN and AKT mutations [13,14], PDGFRB and IGFR1 overexpression [15,16], or production of HGF in the microenvironment [17], have been described. Data regarding resistance mechanisms in patients treated with MAPK-targeted therapies should be reinforced
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