Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer

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• 作者：Stefan Eser¹ ; ⁹ ; Nina Reiff¹ ; ⁹ ; Marlena Messer¹ ; ⁹ ; Barbara Seidler¹ ; Kathleen Gottschalk¹ ; Melanie Dobler¹ ; Maren Hieber¹ ; Andreas Arbeiter¹ ; Sabine Klein¹ ; Bo Kong² ; Christoph W. Michalski² ; Anna Melissa Schlitter³ ; Irene Esposito³ ; ⁸ ; Alexander J. Kind⁴ ; Lena Rad⁵ ; Angelika E. Schnieke⁴ ; Manuela Baccarini⁶ ; Dario R. Alessi⁷ ; Roland Rad¹ ; ⁵ ; ⁸ ; Roland M. Schmid¹ ; ⁸ ; Gü ; nter Schneider¹ ; Dieter Saur¹ ; ⁸ ; ^{dieter.saur@lrz.tum.de}
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：18 March, 2013
• 年：2013
• 卷：23
• 期：3
• 页码：406-420
• 全文大小：4241 K

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Summary

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.