Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
Pubmed ID: 24055054 RIS Download
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on September 23,2022. Software for DNA sequencing analysis that integates with Sanger Sequencing files generated by Applied Biosystems Genetic Analyzers, MegaBACE, and Beckman CEQ electrophoresis systems. It can be used to find single nucleotide polymorphisms (SNPs), insertions and deletions (INDELS), and somatic mutations in direct sequencing, PCR sequencing, mitochondrial DNA sequencing, and resequencing projects.
View all literature mentionsSoftware package that integrates genome wide genetic variation with epigenetic data to identify collaborative transcription factor pairs. Optimized to work with chromatin accessibility assays such as ATAC-seq or DNase I hypersensitivity, as well as transcription factor binding data collected by ChIP-seq. Used to identify combinations of cell type specific transcription factors while simultaneously interpreting functional effects of non-coding genetic variation.
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