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A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
- Source :
- Cancer discovery, vol 2, iss 8, Cancer discovery
- Publication Year :
- 2012
- Publisher :
- American Association for Cancer Research (AACR), 2012.
-
Abstract
- KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here, we show that expression of BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H result in lethal PDA. We tested pharmacologic inhibitors of RAS effectors against multiple human PDA cell lines. Mitogen-activated protein (MAP)/extracellular signal–regulated (ERK) kinase (MEK) inhibition was highly effective both in vivo and in vitro and was synergistic with AKT inhibition in most cell lines tested. We show that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA. Significance: PDA is difficult to treat, in large part, due to recurrent mutations in the KRAS gene. Here, we define rational treatment approaches for the disease achievable today with existing drug combinations by thorough genetic and pharmacologic dissection of the major KRAS effector pathways, RAF→MEK→ERK and phosphoinositide 3′-kinase (PI3′K)→AKT. Cancer Discov; 2(8); 685–93. ©2012 AACR. Read the Commentary on this article by Hanrahan et al., p. 666. This article is highlighted in the In This Issue feature, p. 653.
- Subjects :
- health care facilities, manpower, and services
Pancreatic Intraepithelial Neoplasia
Mitogen-activated protein kinase kinase
Cell Transformation
Mice
0302 clinical medicine
Extracellular Signal-Regulated MAP Kinases
ras
Cancer
0303 health sciences
Tumor
Effector
Immunohistochemistry
3. Good health
Cell Transformation, Neoplastic
Oncology
Pancreatic Ductal
030220 oncology & carcinogenesis
Carcinoma, Pancreatic Ductal
Proto-Oncogene Proteins B-raf
congenital, hereditary, and neonatal diseases and abnormalities
MAP Kinase Signaling System
Immunoblotting
Oncology and Carcinogenesis
education
Biology
Article
Cell Line
Pancreatic Cancer
03 medical and health sciences
Rare Diseases
In vivo
Cell Line, Tumor
health services administration
Genetics
Animals
Humans
Protein kinase B
030304 developmental biology
Mitogen-Activated Protein Kinase Kinases
Neoplastic
Carcinoma
In vitro
Pancreatic Neoplasms
Genes, ras
Good Health and Well Being
Genes
Cell culture
Immunology
Cancer research
Digestive Diseases
Subjects
Details
- ISSN :
- 21598290 and 21598274
- Volume :
- 2
- Database :
- OpenAIRE
- Journal :
- Cancer Discovery
- Accession number :
- edsair.doi.dedup.....eebf68b5ef6241da75f4d02686e6d6ea