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Drug resistance is a major obstacle to curative cancer therapies, and increased understanding of the molecular events contributing to resistance would enable better prediction of therapy response, as well as contribute to new targets for combination therapy. Here we have analyzed the early molecular response to epidermal growth factor receptor (EGFR) inhibition using RNA sequencing data covering 13,486 genes and mass spectrometry data covering 10,138 proteins. This analysis revealed a massive response to EGFR inhibition already within the first 24 h, including significant regulation of hundreds of genes known to control downstream signaling, such as transcription factors, kinases, phosphatases and ubiquitin E3-ligases. Importantly, this response included upregulation of key genes in multiple oncogenic signaling pathways that promote proliferation and survival, such as ERBB3, FGFR2, JAK3, and BCL6, indicating an early adaptive response to EGFR inhibition. Using a library of more than 500 approved and experimental compounds in a combination therapy screen, we could show that several kinase inhibitors with targets including JAK3 and FGFR2 increased the response to EGFR inhibitors. Further, we investigated the functional impact of BCL6 upregulation in response to EGFR inhibition using siRNA-based silencing of BCL6. Proteomics profiling revealed that BCL6 inhibited transcription of multiple target genes including p53, resulting in reduced apoptosis which implicates BCL6 upregulation as a new EGFR inhibitor treatment escape mechanism. Finally, we demonstrate that combined treatment targeting both EGFR and BCL6 act synergistically in killing lung cancer cells. In conclusion, or data indicates that multiple different adaptive mechanisms may act in concert to blunt the cellular impact of EGFR inhibition, and we suggest BCL6 as a potential target for EGFR inhibitor-based combination therapy.
Pubmed ID: 32234966
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Bioinformatics and cheminformatics database that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
View all literature mentionsInternational functional genomics data collection generated from microarray or next-generation sequencing (NGS) platforms. Repository of functional genomics data supporting publications. Provides genes expression data for reuse to the research community where they can be queried and downloaded. Integrated with the Gene Expression Atlas and the sequence databases at the European Bioinformatics Institute. Contains a subset of curated and re-annotated Archive data which can be queried for individual gene expression under different biological conditions across experiments. Data collected to MIAME and MINSEQE standards. Data are submitted by users or are imported directly from the NCBI Gene Expression Omnibus.
View all literature mentionsA data repository for proteomic data sets. The ProteomeExchange consortium, as a whole, aims to provide a coordinated submission of MS proteomics data to the main existing proteomics repositories, as well as to encourage optimal data dissemination. ProteomeXchange provides access to a number of public databases, and users can access and submit data sets to the consortium's PRIDE database and PASSEL/PeptideAtlas.
View all literature mentionsA commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.
View all literature mentionsAn algorithm to align LC-MS samples and to match corresponding ion species across samples.
View all literature mentionsSoftware that enables rapid tool creation by providing a robust, pluggable development framework that simplifies and unifies data file access, and performs standard proteomics and LCMS dataset computations.
View all literature mentionsIntegrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.
View all literature mentionsSoftware package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.
View all literature mentionsPercolator post-processes the results of a shotgun proteomics database search program, re-ranking peptide-spectrum matches so that the top of the list is enriched for correct matches. Shotgun proteomics uses liquid chromatography-tandem mass spectrometry to identify proteins in complex biological samples. We describe an algorithm, called Percolator, for improving the rate of peptide identifications from a collection of tandem mass spectra. Percolator uses semi-supervised machine learning to discriminate between correct and decoy spectrum identifications, correctly assigning peptides to 17% more spectra from a tryptic dataset and up to 77% more spectra from non-tryptic digests, relative to a fully supervised approach. The yeast-01 data is available in tab delimetered format. The SEQUEST parameter file and target database for the yeast and worm data are also available.
View all literature mentionsCell line HCC827 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A-431 is a Cancer cell line with a species of origin Homo sapiens (Human)
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