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BET inhibitors exhibit broad activity in cancer models, making predictive biomarkers challenging to define. Here we investigate the biomarkers of activity of the clinical BET inhibitor GSK525762 (I-BET; I-BET762) across cancer cell lines and demonstrate that KRAS mutations are novel resistance biomarkers. This finding led us to combine BET with RAS pathway inhibition using MEK inhibitors to overcome resistance, which resulted in synergistic effects on growth and survival in RAS pathway mutant models as well as a subset of cell lines lacking RAS pathway mutations. GSK525762 treatment up-regulated p-ERK1/2 levels in both RAS pathway wild-type and mutant cell lines, suggesting that MEK/ERK pathway activation may also be a mechanism of adaptive BET inhibitor resistance. Importantly, gene expression studies demonstrated that the BET/MEK combination uniquely sustains down-regulation of genes associated with mitosis, leading to prolonged growth arrest that is not observed with either single agent therapy. These studies highlight a potential to enhance the clinical benefit of BET and MEK inhibitors and provide a strong rationale for clinical evaluation of BET/MEK combination therapies in cancer.
Pubmed ID: 29674704
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Software repository for R packages related to analysis and comprehension of high throughput genomic data. Uses separate set of commands for installation of packages. Software project based on R programming language that provides tools for analysis and comprehension of high throughput genomic data.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE, documented on February 1st, 2022. Software application for genetic analysis of classical biometric traits like blood pressure or height that are caused by a combination of polygenic inheritance and complex environmental forces. (entry from Genetic Analysis Software)
View all literature mentionsSoftware environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.
View all literature mentionsSoftware package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.
View all literature mentionsSoftware R package of functions and classes for the analysis of oligonucleotide arrays manufactured by Affymetrix. Used to process probe level data and for exploratory oligonucleotide array analysis.
View all literature mentionsSoftware R and Python package for comparison and visualization of biological identifiers lists using area-proportional Venn diagrams. Also offers option to map Entrez and/or Affymetrix IDs to Ensembl IDs. In SVG mode, text and numbers can be dragged and dropped. Used to create area-proportional Venn diagram of 2 or 3 circles.
View all literature mentionsCell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)
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