Efemp1 and p27Kip1 modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models
| العنوان: | Efemp1 and p27Kip1 modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models |
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| المؤلفون: | Günter Schneider, Philipp Eser, Roland M. Schmid, Dieter Saur, Philipp Pagel, Stefan Eser, Barbara Seidler, Marlena Messer, Melanie Szameitat, Maximilian Reichert, Mariel C. Paul, Patrick Wenzel, Sandra Diersch, Irene Esposito |
| المصدر: | Oncotarget Web of Science |
| بيانات النشر: | Impact Journals LLC, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | endocrine system diseases, pancreatic cancer, Cell Growth Processes, Biology, P110α, medicine.disease_cause, Transfection, PI3K, Efemp1, Mice, Pancreatic cancer, Cell Line, Tumor, medicine, Carcinoma, Animals, Humans, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, Mice, Knockout, Extracellular Matrix Proteins, Kinase, TOR Serine-Threonine Kinases, Cancer, p27, medicine.disease, Discovery and development of mTOR inhibitors, Xenograft Model Antitumor Assays, digestive system diseases, Pancreatic Neoplasms, Disease Models, Animal, Oncology, Immunology, Cancer research, Bez235, KRAS, Phosphatidylinositol 3-Kinase, Cyclin-Dependent Kinase Inhibitor p27, Research Paper, Carcinoma, Pancreatic Ductal, Signal Transduction |
| الوصف: | // Sandra Diersch 1 , Patrick Wenzel 1 , Melanie Szameitat 1 , Philipp Eser 2 , Mariel C. Paul 1 , Barbara Seidler 1 , Stefan Eser 1 , Marlena Messer 1 , Maximilian Reichert 3 , Philipp Pagel 4 , Irene Esposito 5 , Roland M. Schmid 1 , Dieter Saur 1 , Gunter Schneider 1 1 II. Medizinische Klinik, Technische Universitat Munchen, Munchen, Germany 2 Gene Center Munich, Ludwig-Maximilians-Universitat (LMU) Munchen, Munchen, 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 fur Allgemeine Pathologie und Pathologische Anatomie, Technische Universitat Munchen, Munchen, Germany Correspondence: Gunter Schneider, email: // Keywords : pancreatic cancer, PI3K, Efemp1, p27, Bez235 Received : February 04, 2013 Accepted : February 25, 2013 Published : February 26, 2013 Abstract 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 Kras G12D - and PI3K (p110α H1047R )-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 Kras G12D - and PI3K (p110α H1047R )-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 p27 Kip1 . In a murine Kras G12D -driven PDAC model, p27 Kip1 haploinsufficiency accelerates cancer development in vivo. Furthermore, p27 Kip1 controls Bez235 sensitivity in a gene dose-dependent fashion in murine PDAC cells and lowering of p27 Kip1 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. |
| اللغة: | English |
| تدمد: | 1949-2553 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8754d7d4776682fd83a8f533c9cfce2eTest http://europepmc.org/articles/PMC3712573Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8754d7d4776682fd83a8f533c9cfce2e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19492553 |
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