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| Status |
Public on Mar 06, 2014 |
| Title |
Inhibiting tankyrases sensitizes KRAS mutant cancer cells to MEK inhibitors by FGFR2 feedback signaling |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis and mitosis, offering attractive targets for anti-cancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors in KRAS mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and anti-tumor activity both in vitro and in vivo than effects observed by previously reported MEK inhibitor combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS mutant cancers by suppressing a newly discovered resistance mechanism.
This experiment is designed to detect genes differentially expressed in the combination treatment compared to others
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| Overall design |
SW480 cells were seeded in 10cm dishes and treated for 4h and 16h with DMSO, TNKS inhibitor (TNKSi : NVP-TNKS656), MEK inhibitor (MEKi : AZD6244) or the combination of both at 1uM final
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| Contributor(s) |
Schoumacher M, Hurov KE, Lehár J, Yan-Neale Y, Mishina Y, Sonkin D, Korn JM, Flemming D, Jones MD, Antonakos B, Cooke VG, Steiger J, Ledell J, Stump M, Sellers WR, Danial NN, Shao W |
| Citation(s) |
24747911 |
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| Submission date |
Mar 05, 2014 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Joshua M Korn |
| E-mail(s) |
joshkorn@gmail.com
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| Organization name |
Novartis
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| Street address |
250 Mass Ave
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02141 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA240233 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE55624_RAW.tar |
92.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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