| 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]
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| Organism(s): |
Homo sapiens
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| 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.]
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| Design(s): |
transcription profiling by array
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| Experimental factor(s): |
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| diclofenac treatment
2
recorded
|
|
|
|
diclofenac
none
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| cell line
3
recorded
|
|
|
|
VMM39
SLM2
DM331
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| mutation
3
recorded
|
|
|
|
Ras
WT
Braf
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| sorafenib treatment
2
recorded
|
|
|
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sorafenib
none
|
|
| Publication(s): |
Roller DG, Axelrod M, Capaldo BJ, Jensen K, Mackey A, Weber MJ, Gioeli D
Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma.
PubMed:22962324
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| Sample attribute(s): |
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| Cell line type
1
recorded
|
|
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melanoma
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| cell line
3
recorded
|
|
|
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VMM39
SLM2
DM331
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| mutation
3
recorded
|
|
|
|
Ras
WT
Braf
|
| Label
1
recorded
|
|
|
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biotin
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| organism
1
recorded
|
|
|
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Homo sapiens
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|
| Contact(s): |
Stephen Turner Daniel GioeliDevin Roller
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| Release Date: |
12/6/2012
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| Submission Date: |
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| Metadata Downloads |
Download Study Metadata as ISAtabDownload Study Metadata as ISAtab
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| Assay Downloads |
| transcription profiling using DNA microarray
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| 24 assays |
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