Abstract |
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) 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 antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi 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.
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Authors | Marie Schoumacher, Kristen E Hurov, Joseph Lehár, Yan Yan-Neale, Yuji Mishina, Dmitriy Sonkin, Joshua M Korn, Daisy Flemming, Michael D Jones, Brandon Antonakos, Vesselina G Cooke, Janine Steiger, Jebediah Ledell, Mark D Stump, William R Sellers, Nika N Danial, Wenlin Shao |
Journal | Cancer research
(Cancer Res)
Vol. 74
Issue 12
Pg. 3294-305
(Jun 15 2014)
ISSN: 1538-7445 [Electronic] United States |
PMID | 24747911
(Publication Type: Journal Article)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- Acetamides
- Aminopyridines
- Aniline Compounds
- KRAS protein, human
- Morpholines
- N-(cyclopropylmethyl)-2-(4-(4-methoxybenzoyl)piperidin-1-yl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano(4,3-d)pyrimidin-2-yl)methyl)acetamide
- NVP-BKM120
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins
- Pyrimidinones
- Quinazolines
- Sulfonamides
- Thiazoles
- Alpelisib
- Erlotinib Hydrochloride
- Tankyrases
- TNKS protein, human
- FGFR2 protein, human
- Receptor, Fibroblast Growth Factor, Type 2
- MAP Kinase Kinase Kinases
- Proto-Oncogene Proteins p21(ras)
- ras Proteins
- navitoclax
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Topics |
- Acetamides
(administration & dosage)
- Aminopyridines
(administration & dosage)
- Aniline Compounds
(administration & dosage)
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, therapeutic use)
- Cell Line, Tumor
- Drug Synergism
- Erlotinib Hydrochloride
- Feedback, Physiological
- Female
- Humans
- MAP Kinase Kinase Kinases
(antagonists & inhibitors, metabolism)
- Mice
- Mice, Nude
- Morpholines
(administration & dosage)
- Mutation
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Proto-Oncogene Proteins
(genetics)
- Proto-Oncogene Proteins p21(ras)
- Pyrimidinones
(administration & dosage)
- Quinazolines
(administration & dosage)
- Receptor, Fibroblast Growth Factor, Type 2
(antagonists & inhibitors, metabolism)
- Signal Transduction
- Sulfonamides
(administration & dosage)
- Tankyrases
(antagonists & inhibitors, metabolism)
- Thiazoles
(administration & dosage)
- Xenograft Model Antitumor Assays
- ras Proteins
(genetics)
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