Efemp1 and p27Kip1 modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models
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Sandra Diersch1, Patrick Wenzel1, Melanie Szameitat1, Philipp Eser2, Mariel C. Paul1, Barbara Seidler1, Stefan Eser1, Marlena Messer1, Maximilian Reichert3, Philipp Pagel4, Irene Esposito5, Roland M. Schmid1, Dieter Saur1, Günter Schneider1
1 II. Medizinische Klinik, Technische Universität München, München, Germany
2 Gene Center Munich, Ludwig-Maximilians-Universität (LMU) München, München, Germany
3 Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA
4 numares GmbH, Regensburg, Germany
5 Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, München, Germany
Günter Schneider, email:
Keywords: pancreatic cancer, PI3K, Efemp1, p27, Bez235
Received: February 04, 2013 Accepted: February 25, 2013 Published: February 26, 2013
Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease with a poor prognosis and targeted therapies have failed in the clinic so far. Several evidences point to the phosphatidylinositol 3-kinase (PI3K)-mTOR pathway as a promising signaling node for targeted therapeutic intervention. Markers, which predict responsiveness of PDAC cells towards PI3K inhibitors are unknown. However, such markers are needed and critical to better stratify patients in clinical trials.
We used a large murine KrasG12D- and PI3K (p110αH1047R)-driven PDAC cell line platform to unbiased define modulators of responsiveness towards the dual PI3K-mTOR inhibitor Bez235. In contrast to other tumor models, we show that KrasG12D- and PI3K (p110αH1047R)-driven PDAC cell lines are equally sensitive towards Bez235. In an unbiased approach we found that the extracellular matrix protein Efemp1 controls sensitivity of murine PDAC cells towards Bez235. We show that Efemp1 expression is connected to the cyclin-dependent kinase inhibitor p27Kip1. In a murine KrasG12D-driven PDAC model, p27Kip1 haploinsufficiency accelerates cancer development in vivo. Furthermore, p27Kip1 controls Bez235 sensitivity in a gene dose-dependent fashion in murine PDAC cells and lowering of p27Kip1 decreases Bez235 responsiveness in murine PDAC models.
Together, we define the Efemp1-p27Kip1 axis as a potential marker module of PDAC cell sensitivity towards dual PI3K-mTOR inhibitors, which might help to better stratify patients in clinical trials.
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