BRAF and NRAS mutation status was determined retrospectively in available tissue specimens from patients with melanoma who were enrolled in a phase 1 trial of selumetinib in combination with 1 of 4 drugs (dacarbazine, docetaxel, temsirolimus, or erlotinib).
The BRAF oncogene has recently emerged as a critical regulator of this process in melanoma, bringing to the fore the importance of metabolic reprogramming in the pathogenesis and treatment of metastatic melanoma.
Overall, these data support a key role of the ERK5 pathway for melanoma growth in vitro and in vivo and suggest that targeting ERK5, alone or in combination with BRAF-MEK1/2 inhibitors, might represent a novel approach for melanoma treatment.
These data suggest that MITF is an anti-proliferation factor that is down-regulated by B-RAF signaling and that this is a crucial event for the progression of melanomas that harbor oncogenic B-RAF.
Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth inhibitory effects of CDDO-Me and induced apoptosis in A375, a BRAF mutated melanoma line (P < 0.001).
To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.
Targeting of mutated BRAF kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients, underscoring the particular role of this oncogene in melanoma biology.
Taken together, these findings indicate that NRAS-mutant melanoma share with BRAF-mutant melanoma the potential to regulate apoptosis upon MEK inhibition through WNT3A and dynamic regulation of cellular AXIN1.
Previously, we identified the plasma membrane Ca<sup>2+</sup> ATPase 4b (PMCA4b) as a metastasis suppressor in BRAF-mutant melanomas and found that mutant BRAF inhibition increased the expression of the pump, which then inhibited the migratory and metastatic capability of the cells.
Collectively, our data suggest that UI-152 may be an effective B-Raf inhibitor and a potential therapeutic strategy for B-Raf(WT) and Ras mutant melanoma.
BRAF mutation frequency ranges from 40 to 60% depending on melanoma clinical characteristics and detection technique used.Intertumoral heterogeneity could lead to misinterpretation of BRAF mutational status; this is especially important if testing is performed on primary specimens, when metastatic lesions are unavailable.Aim of this study was to identify the best combination of methods for detecting BRAF mutations (among peptide nucleic acid - PNA-clamping real-time PCR, immunohistochemistry and capillary sequencing) and investigate BRAF mutation heterogeneity in a series of 100 primary melanomas and a subset of 25 matched metastatic samples.Overall, we obtained a BRAF mutation frequency of 62%, based on the combination of at least two techniques.
Anti-tumor effects of the combination of the BRAF inhibitor (BRAFi) dabrafenib and GSK2141795B (AKTi) in a panel of 23 BRAF mutated melanoma cell lines were evaluated on growth inhibition by an ATP-based luminescent assay, on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot.
We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group).
Our analysis of data has demonstrated that combined BRAF and MEK inhibitor-based treatment is associated with an increased risk of all-grade rash and a decreased risk of all-grade and high-grade HK, SP, alopecia, cSCC, HFS, and PR compared with single BRAF inhibitor alone in melanoma patients.