title: Efemp1 and p27(Kip1) modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models.
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-p27(Kip1) 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.
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Diersch
authors.forename: Patrick
authors.initials: P
authors.lastname: Wenzel
authors.forename: Melanie
authors.initials: M
authors.lastname: Szameitat
authors.forename: Philipp
authors.initials: P
authors.lastname: Eser
authors.forename: Mariel C
authors.initials: MC
authors.lastname: Paul
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.forename: Stefan
authors.initials: S
authors.lastname: Eser
authors.forename: Marlena
authors.initials: M
authors.lastname: Messer
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.forename: Philipp
authors.initials: P
authors.lastname: Pagel
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C119630:EFEMP1 protein, human; C492278:Efemp1 protein, mouse; D016326:Extracellular Matrix Proteins; D047428:Protein Kinase Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases