Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells.
Considering the antitumor activity of benzothiazolic derivatives, this study aimed to demonstrate the action of benzothiazolic (E)-2-((2-(benzo[d]thiazol-2-yl)hydrazono)methyl)-4-nitrophenol (AFN01) against three established human melanoma cell lines that recapitulate the molecular landscape of the disease in terms of its genetic alterations and mutations, such as the TP53, NRAS and B-RAF genes.
We have treated 45 patients with V600 mutated melanoma including patients with V600R mutation between July 2011 and October 2012 with the selective BRAF inhibitor dabrafenib (n=43) or vemurafenib (n=2) via a compassionate access programme.
In this review article, we have discussed application of "DNA damage-targeted mutagenicity" of solar UV-irradiation for determining the mechanistic involvement of sunlight UV in BRAF V600 mutagenesis in human melanoma.
We found that HGF mediates resistance of cMET-expressing BRAF mutant melanoma cells to PLX4032-induced apoptosis through downregulation of PUMA and BIM rather than by increasing the expression of pro-survival BCL-2-like proteins.
In the 8 years following the discovery of BRAF mutations in 50-60% of advanced melanomas, only recently have potent and selective inhibitors of this intracellular signaling molecule shown efficacy from early clinical testing.
Gene expression analysis using pre-treatment tumor samples supports high ALDH1A3 expression before BRAF/MEK inhibitor treatment as predictive of better treatment response in BRAF-mutant melanoma patients.
Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2.