Mutations in the serine/threonine kinase BRAF are found in more than 60% of melanomas. The most prevalent melanoma mutation is BRAF(V600E), which constitutively activates downstream MAPK signalling. Vemurafenib is a potent RAF kinase inhibitor with remarkable clinical activity in BRAF(V600E)-positive melanoma tumours. However, patients rapidly develop resistance to vemurafenib treatment. One resistance mechanism is the emergence of BRAF alternative splicing isoforms leading to elimination of the RAS-binding domain. Here we identify interference with pre-mRNA splicing as a mechanism to combat vemurafenib resistance. We find that small-molecule pre-mRNA splicing modulators reduce BRAF3-9 production and limit in-vitro cell growth of vemurafenib-resistant cells. In xenograft models, interference with pre-mRNA splicing prevents tumour formation and slows growth of vemurafenib-resistant tumours. Our results identify an intronic mutation as the molecular basis for a RNA splicing-mediated RAF inhibitor resistance mechanism and we identify pre-mRNA splicing interference as a potential therapeutic strategy for drug resistance in BRAF melanoma.
Pubmed ID: 25971842 RIS Download
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This server provides programs, web services, and databases, related to our work on RNA secondary structures. For general information and other offerings from our group see the main TBI web server. With the 1st of May 2009 we updated our servers to the Vienna RNA package version 1.8.2! The Vienna RNA Servers: * RNAfold server predicts minimum free energy structures and base pair probabilities from single RNA or DNA sequences. * RNAalifold server predicts consensus secondary structures from an alignment of several related RNA or DNA sequences. You need to upload an alignment. * RNAinverse server allows you to design RNA sequences for any desired target secondary structure. * RNAcofold server allows you to predict the secondary structure of a dimer. * RNAup server allows you to predict the accessibility of a target region. * LocARNA server generates structural alignments from a set of sequences. In collaboration with the Bioinformatics Group Freiburg. * barriers server allows you to get insights into RNA folding kinetics. * RNAz server will assist you in detecting thermodynamically stable and evolutionarily conserved RNA secondary structures in multiple sequence alignments. * Structure conservation analysis server will assist you in detecting evolutionarily conserved RNA secondary structures in multiple sequence alignments. * RNAstrand server allows you to predict the reading direction of evolutionarily conserved RNA secondary structures. * RNAxs server assists you in siRNA design. * Bcheck predicts rnpB genes Downloads Get the Source code for: * the Vienna RNA Package, our basic RNA secondary structure analysis software. * The ALIDOT package for finding conserved structure motifs (add-on) * The barriers program for analysis of RNA folding landscapes. Databases * Atlas of conserved Viral RNA Structures found by ALIDOT
View all literature mentionsAn independent, nonprofit organization focused on mammalian genetics research to advance human health. Their mission is to discover the genetic basis for preventing, treating, and curing human disease, and to enable research for the global biomedical community. Jackson Laboratory breeds and manages colonies of mice as resources for other research institutions and laboratories, along with providing software and techniques. Jackson Lab also conducts genetic research and provides educational material for various educational levels.
View all literature mentionsA web-based resource that facilitates rapid analysis of exon sequences to identify putative exonic splicing enhancers (ESEs) responsive to the human SR proteins SF2/ASF, SC35, SRp40 and SRp55, and to predict whether exonic mutations disrupt such elements.
View all literature mentionsCell line U2OS is a Cancer cell line with a species of origin Homo sapiens (Human)
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