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

Stefan Eser, Nina Reiff, Marlena Messer, Barbara Seidler, Kathleen Gottschalk, Melanie Dobler, Maren Hieber, Andreas Arbeiter, Sabine Klein, Bo Kong, Christoph W. Michalski, Anna Melissa Schlitter, Irene Esposito, Alexander J. Kind, Lena Rad, Angelika E. Schnieke, Manuela Baccarini, Dario R. Alessi, Roland Rad, Roland M. SchmidGuenter Schneider, Dieter Saur

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    179 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)406-420
    Number of pages15
    JournalCancer Cell
    Volume23
    Issue number3
    DOIs
    Publication statusPublished - 2013

    Keywords

    • RAS ONCOGENE
    • TUMOR-SUPPRESSOR
    • MICE
    • DUCTAL ADENOCARCINOMA
    • PI3K
    • C-RAF
    • IN-VIVO
    • EGF RECEPTOR
    • TUMORIGENESIS
    • MOUSE MODEL

    Cite this

    Eser, S., Reiff, N., Messer, M., Seidler, B., Gottschalk, K., Dobler, M., Hieber, M., Arbeiter, A., Klein, S., Kong, B., Michalski, C. W., Schlitter, A. M., Esposito, I., Kind, A. J., Rad, L., Schnieke, A. E., Baccarini, M., Alessi, D. R., Rad, R., ... Saur, D. (2013). Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer. Cancer Cell, 23(3), 406-420. https://doi.org/10.1016/j.ccr.2013.01.023