ONTOLOGY SOURCE REFERENCE Term Source Name "ArrayExpress" "EFO" "NCBITaxon" "MSH" "DOID" "CHEBI" Term Source File "http://www.ebi.ac.uk/arrayexpress/" "http://www.ebi.ac.uk/efo/efo.owl" "http://bioportal.bioontology.org/ontologies/47845" "http://bioportal.bioontology.org/ontologies/46836" "http://bioportal.bioontology.org/ontologies/50657" "http://bioportal.bioontology.org/ontologies/50526" Term Source Version "" "" "47845" "46836" "50657" "50526" Term Source Description "" "" "National Center for Biotechnology Information (NCBI) Organismal Classification" "Medical Subject Headings" "Human Disease Ontology" "Chemical Entities of Biological Interest Ontology" INVESTIGATION Investigation Identifier "" Investigation Title "" Investigation Description "" Investigation Submission Date "" Investigation Public Release Date "" Comment [Created with configuration] "" Comment [Last Opened With Configuration] "" INVESTIGATION PUBLICATIONS Investigation PubMed ID "" Investigation Publication DOI "" Investigation Publication Author List "" Investigation Publication Title "" Investigation Publication Status "" Investigation Publication Status Term Accession Number "" Investigation Publication Status Term Source REF "" INVESTIGATION CONTACTS Investigation Person Last Name "" Investigation Person First Name "" Investigation Person Mid Initials "" Investigation Person Email "" Investigation Person Phone "" Investigation Person Fax "" Investigation Person Address "" Investigation Person Affiliation "" Investigation Person Roles "" Investigation Person Roles Term Accession Number "" Investigation Person Roles Term Source REF "" STUDY Study Identifier "E-GEOD-39192" Study Title "Transcriptional profiling of three human melanoma cell lines treated with the NSAID diclofenac and/or the anticancer drug sorafenib. [original title: Synthetic lethal screening with small molecule inhibitors provides a pathway to rational combination therapies for melanoma]" Study Description "Three cell lines -- VMM39 (NRAS mutant), SLM2, and DM331 (BRAF mutant) -- were treated with diclofenac and/or sorafenib or a no drug control medium. Total: 24 samples (12 combinations, run in duplicate). [original description: Recent data demonstrate that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways. This network model suggests why inhibition of a single component of a canonical pathway, even when targeting a mutationally activated driver of cancer, has insufficiently dramatic effects on the treatment of cancer. The biological outcome of signals propagated through a network is inherently more robust and resistant to inhibition of a single network component due to compensatory and redundant signaling events. In this study, we performed a functional chemical genetic screen analogous to synthetic lethal screening in yeast genetics to identify novel interactions between signaling inhibitors that would not be predicted based on our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. Among the most robust and surprising results was synergy between sorafenib, a multi-kinase inhibitor with activity against Raf, and diclofenac, a non-steroidal anti-inflammatory drug (NSAID). This synergy did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. The NSAIDs celecoxib and ibuprofen could qualitatively substitute for diclofenac. Similarly, the MEK inhibitor PD325901 and the Raf inhibitor RAF265 could qualitatively substitute for sorafenib. These drug substitution experiments suggest that inhibition of cyclo-oxygenase and MAP kinase signaling are components of the observed synergistic cytotoxicity. Genome-wide expression profiling demonstrates synergy-specific down-regulation of survival-related genes. This study provides proof of principle that synthetic lethal screening can uncover novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially depending on unexplored components of the cell genotype. RNA from VMM39, DM331, and SLM2 cells with/without mutations in Ras and/or Braf, treated with Sorafenib and/or Diclofenac.]" Comment[Study Grant Number] "" Comment[Study Funding Agency] "" Study Submission Date "" Study Public Release Date "2012-12-06" Study File Name "s_E-GEOD-39192_study_samples.txt" STUDY DESIGN DESCRIPTORS Study Design Type "transcription profiling by array" Study Design Type Term Accession Number "" Study Design Type Term Source REF "" STUDY PUBLICATIONS Study PubMed ID "22962324" Study Publication DOI "10.1158/1535-7163.MCT-12-0461" Study Publication Author List "Roller DG, Axelrod M, Capaldo BJ, Jensen K, Mackey A, Weber MJ, Gioeli D" Study Publication Title "Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma." Study Publication Status "" Study Publication Status Term Accession Number "" Study Publication Status Term Source REF "" STUDY FACTORS Study Factor Name "cell line" "diclofenac treatment" "mutation" "sorafenib treatment" Study Factor Type "cell line" "treatment" "mutation" "treatment" Study Factor Type Term Accession Number "" "" "" "" Study Factor Type Term Source REF "" "" "" "" STUDY ASSAYS Study Assay File Name "a_E-GEOD-39192_GeneChip_assay.txt" Study Assay Measurement Type "transcription profiling" Study Assay Measurement Type Term Accession Number "" Study Assay Measurement Type Term Source REF "" Study Assay Technology Type "DNA microarray" Study Assay Technology Type Term Accession Number "" Study Assay Technology Type Term Source REF "" Study Assay Technology Platform "" STUDY PROTOCOLS Study Protocol Name "P-GSE39192-2" "P-GSE39192-3" "P-GSE39192-4" "P-GSE39192-5" "P-GSE39192-6" "P-GSE39192-7" "P-GSE39192-1" Study Protocol Type "grow" "nucleic_acid_extraction" "labeling" "hybridization" "image_acquisition" "feature_extraction" "bioassay_data_transformation" Study Protocol Type Term Accession Number "" "" "" "" "" "" "" Study Protocol Type Term Source REF "" "" "" "" "" "" "" Study Protocol Description "SLM2, VMM39, and DM331 cells were plated and incubated overnight before being treated, in duplicate, with inhibitors or vehicle control in phenol red-free RPMI Medium 1640 without fetal bovine serum for 8 hours at 37° C. Cells were placed on ice and rinsed with cold 1x PBS." "Cells were collected and RNA was isolated using the Qiashredder (Qiagen, Valencia, CA) and RNeasy Mini Kit (Qiagen, Valencia, CA)." "The gene array was performed using Illumina 3’IVT human HT-12 BeadChip arrays by Gene Analysis (Durham, NC)." "The gene array was performed using Illumina 3’IVT human HT-12 BeadChip arrays by Gene Analysis (Durham, NC)." "The gene array was performed using Illumina 3’IVT human HT-12 BeadChip arrays by Gene Analysis (Durham, NC)." "Quantile normalized and log2-transformed" "ID_REF = VALUE = Quantile normalized and log2-transformed hybridization intensities Detection Pval = " Study Protocol URI "" "" "" "" "" "" "" Study Protocol Version "" "" "" "" "" "" "" Study Protocol Parameters Name "" "" "" "" "" "" "" Study Protocol Parameters Name Term Accession Number "" "" "" "" "" "" "" Study Protocol Parameters Name Term Source REF "" "" "" "" "" "" "" Study Protocol Components Name "" "" "" "" "" "" "" Study Protocol Components Type "" "" "" "" "" "" "" Study Protocol Components Type Term Accession Number "" "" "" "" "" "" "" Study Protocol Components Type Term Source REF "" "" "" "" "" "" "" STUDY CONTACTS Study Person Last Name "Turner" "Roller" "Gioeli" Study Person First Name "Stephen" "Devin" "Daniel" Study Person Mid Initials "" "" "" Study Person Email "geo@ncbi.nlm.nih.gov" "" "" Study Person Phone "" "" "" Study Person Fax "" "" "" Study Person Address "UVA, PO Box 800741, Charlottesville, VA, USA" "" "" Study Person Affiliation "UVA" "" "" Study Person Roles "submitter" "" "" Study Person Roles Term Accession Number "" "" "" Study Person Roles Term Source REF "" "" "" Comment[Study Person REF] "" "" ""