Abstract | PURPOSE:
Gemcitabine, a nucleoside analogue, is an important treatment for locally advanced and metastatic pancreatic ductal adenocarcinoma (PDAC) but provides only modest survival benefit. Targeting downstream effectors of the RAS/ERK signaling pathway by direct inhibition of MEK1/2 proteins is a promising therapeutic strategy, as aberrant activation of this pathway occurs frequently in PDAC. In this study, the ability of pimasertib, a selective allosteric MEK1/2 inhibitor, to enhance gemcitabine efficacy was tested and the molecular mechanism of their interaction was investigated. EXPERIMENTAL DESIGN: RESULTS: CONCLUSIONS: These results confirm an important role of RRM1 in gemcitabine response and indicate MEK as a potential target to sensitize gemcitabine therapy for PDAC. Clin Cancer Res; 21(24); 5563-77. ©2015 AACR.
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Authors | Francesca Vena, Eleonora Li Causi, Manuel Rodriguez-Justo, Samantha Goodstal, Thorsten Hagemann, John A Hartley, Daniel Hochhauser |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 21
Issue 24
Pg. 5563-77
(Dec 15 2015)
ISSN: 1557-3265 [Electronic] United States |
PMID | 26228206
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2015 American Association for Cancer Research. |
Chemical References |
- Antineoplastic Agents
- N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
- Protein Kinase Inhibitors
- RNA, Small Interfering
- Tumor Suppressor Proteins
- Deoxycytidine
- Niacinamide
- RRM1 protein, human
- Ribonucleoside Diphosphate Reductase
- Proto-Oncogene Proteins c-mdm2
- MAP2K2 protein, human
- Proto-Oncogene Proteins c-akt
- MAP Kinase Kinase 1
- MAP Kinase Kinase 2
- MAP2K1 protein, human
- Caspases
- Gemcitabine
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Caspases
(metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cell Survival
(drug effects)
- Deoxycytidine
(analogs & derivatives, pharmacology)
- Disease Models, Animal
- Drug Resistance, Neoplasm
(genetics)
- Drug Synergism
- Female
- Gene Knockdown Techniques
- Humans
- MAP Kinase Kinase 1
(antagonists & inhibitors)
- MAP Kinase Kinase 2
(antagonists & inhibitors)
- Mice
- Niacinamide
(analogs & derivatives, pharmacology)
- Pancreatic Neoplasms
(drug therapy, genetics, metabolism, pathology)
- Protein Kinase Inhibitors
(pharmacology)
- Proteolysis
- Proto-Oncogene Proteins c-akt
(metabolism)
- Proto-Oncogene Proteins c-mdm2
(metabolism)
- RNA, Small Interfering
(genetics)
- Ribonucleoside Diphosphate Reductase
- Transplantation, Isogeneic
- Tumor Burden
(drug effects)
- Tumor Suppressor Proteins
(genetics, metabolism)
- Ubiquitination
- Gemcitabine
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