Journal
CANCER CELL
Volume 23, Issue 3, Pages 406-420Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2013.01.023
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Funding
- Deutsche Krebshilfe [108985]
- Helmholtz Preclinical Comprehensive Cancer Center
- Novartis-Stiftung fur therapeutische Forschung
- DFG [SFB824, TP C9]
- MRC [MC_UU_12016/2, MC_U127015387] Funding Source: UKRI
- Medical Research Council [MC_UU_12016/2, MC_U127015387] Funding Source: researchfish
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Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.
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