Grant: Project Grant

Cellular senescence is a stable cell cycle arrest triggered by stresses that can cause cancer. Some cancer causing genes can activate this program in normal cells. The prototype senescence inducer is oncogenic RAS, a gene that is mutated in 30% of human cancers and up to 90 % of pancreatic cancers. We discovered that the strength of RAS signalling through the ERK MAP kinase pathway is the most important factor regulating oncogene induced senescence. RAS induces senescence both in cell culture models and mouse models of pancreatic cancer. Tumors can only form when this senescence barrier is overcome. Attenuation of ERK signalling allows cells with oncogenic ras to bypass senescence and progress into malignant tumors. We propose to counteract the attenuation of ERK signalling in pancreatic cancer by hyperactivating ERK using both genetic and pharmacological tools. Our preliminary data shows that this strategy works both in cell culture and in mice restoring the senescence tumor suppressor response. We will investigate the mechanism by which hyperactive ERK signaling suppress tumor progression in pancreatic cancer cells and identify biomarkers that characterize this tumor suppressor response. We will also conduct genetic studies to identify new targets that can improve ERK-dependent tumor suppression for the eventual treatment of pancreatic cancer.