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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 06, 2012 |
| Title |
Synthetic lethal screening with small molecule inhibitors provides a pathway to rational combination therapies for melanoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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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| Contributor(s) |
Roller D, Gioeli D |
| Citation(s) |
22962324 |
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| Submission date |
Jul 09, 2012 |
| Last update date |
Aug 16, 2018 |
| Contact name |
Stephen Turner |
| Organization name |
Signature Science, LLC
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| Street address |
1670 Discovery Drive
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| City |
Charlottesville |
| State/province |
VA |
| ZIP/Postal code |
22911 |
| Country |
USA |
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| Platforms (1) |
| GPL6947 |
Illumina HumanHT-12 V3.0 expression beadchip |
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| Samples (24)
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| GSM957743 |
Cell line VMM39, mutant status Ras, condition Control 1 |
| GSM957744 |
Cell line VMM39, mutant status Ras, condition Treated with Sorafenib 1 |
| GSM957745 |
Cell line VMM39, mutant status Ras, condition Treated with Diclofenac 1 |
| GSM957746 |
Cell line VMM39, mutant status Ras, condition Treated with Sorafenib+Diclofenac 1 |
| GSM957747 |
Cell line VMM39, mutant status Ras, condition Control 2 |
| GSM957748 |
Cell line VMM39, mutant status Ras, condition Treated with Sorafenib 2 |
| GSM957749 |
Cell line VMM39, mutant status Ras, condition Treated with Diclofenac 2 |
| GSM957750 |
Cell line VMM39, mutant status Ras, condition Treated with Sorafenib+Diclofenac 2 |
| GSM957751 |
Cell line DM331, mutant status Braf, condition Control 1 |
| GSM957752 |
Cell line DM331, mutant status Braf, condition Treated with Sorafenib 1 |
| GSM957753 |
Cell line DM331, mutant status Braf, condition Treated with Diclofenac 1 |
| GSM957754 |
Cell line DM331, mutant status Braf, condition Treated with Sorafenib+Diclofenac 1 |
| GSM957755 |
Cell line DM331, mutant status Braf, condition Control 2 |
| GSM957756 |
Cell line DM331, mutant status Braf, condition Treated with Sorafenib 2 |
| GSM957757 |
Cell line DM331, mutant status Braf, condition Treated with Diclofenac 2 |
| GSM957758 |
Cell line DM331, mutant status Braf, condition Treated with Sorafenib+Diclofenac 2 |
| GSM957759 |
Cell line SLM2, mutant status WT, condition Control 1 |
| GSM957760 |
Cell line SLM2, mutant status WT, condition Treated with Sorafenib 1 |
| GSM957761 |
Cell line SLM2, mutant status WT, condition Treated with Diclofenac 1 |
| GSM957762 |
Cell line SLM2, mutant status WT, condition Treated with Sorafenib+Diclofenac 1 |
| GSM957763 |
Cell line SLM2, mutant status WT, condition Control 2 |
| GSM957764 |
Cell line SLM2, mutant status WT, condition Treated with Sorafenib 2 |
| GSM957765 |
Cell line SLM2, mutant status WT, condition Treated with Diclofenac 2 |
| GSM957766 |
Cell line SLM2, mutant status WT, condition Treated with Sorafenib+Diclofenac 2 |
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| Relations |
| BioProject |
PRJNA170186 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE39192_RAW.tar |
6.2 Mb |
(http)(custom) |
TAR |
| Processed data included within Sample table |
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