title: Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer.
abstract: 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.
authors: Department of Internal Medicine 2, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany.
authors: Stefan
authors: S
authors: Eser
authors: Nina
authors: N
authors: Reiff
authors: Marlena
authors: M
authors: Messer
authors: Barbara
authors: B
authors: Seidler
authors: Kathleen
authors: K
authors: Gottschalk
authors: Melanie
authors: M
authors: Dobler
authors: Maren
authors: M
authors: Hieber
authors: Andreas
authors: A
authors: Arbeiter
authors: Sabine
authors: S
authors: Klein
authors: Bo
authors: B
authors: Kong
authors: Christoph W
authors: CW
authors: Michalski
authors: Anna Melissa
authors: AM
authors: Schlitter
authors: Irene
authors: I
authors: Esposito
authors: Alexander J
authors: AJ
authors: Kind
authors: Lena
authors: L
authors: Rad
authors: Angelika E
authors: AE
authors: Schnieke
authors: Manuela
authors: M
authors: Baccarini
authors: Dario R
authors: DR
authors: Alessi
authors: Roland
authors: R
authors: Rad
authors: Roland M
authors: RM
authors: Schmid
authors: Günter
authors: G
authors: Schneider
authors: Dieter
authors: D
authors: Saur
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D051847:Lithostathine / Q000378:metabolism; D008679:Metaplasia; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007191:Indazoles; D051847:Lithostathine; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D013449:Sulfonamides; D048008:TNF Receptor-Associated Factor 3; D018631:ras Proteins; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C117307:KRAS protein, human; C497617:REG1A protein, human; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse