Efemp1 and p27^Kip1 modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models

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 (p110a^H1047R)-driven PDAC cell line platform to unbiased define modulators of responsiveness towards the dual PI3KmTOR inhibitor Bez235. In contrast to other tumor models, we show that Kras^G12D-and PI3K (p110a^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.