title: Targeting the Ras-ERK pathway in pancreatic adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PAC) stands as the poorest prognostic tumor of the digestive tract with limited therapeutic options. PAC carcinogenesis is associated with the loss of function of tumor suppressor genes such as INK4A, TP53, BRCA2, and DPC4, and only a few activated oncogenes among which K-RAS mutations are the most prevalent. The K-RAS mutation occurs early in PAC carcinogenesis, driving downstream activation of MEK and ERK1/2 which promote survival, invasion, and migration of cancer cells. In PAC models, inhibition of members of the Ras-ERK pathway blocks cellular proliferation and metastasis development. As oncogenic Ras does not appear to be a suitable drug target, inhibitors targeting downstream kinases including Raf and MEK have been developed and are currently under evaluation in clinical trials. In this review, we describe the role of the Ras-ERK pathway in pancreatic carcinogenesis and as a new therapeutic target for the treatment of PAC.
authors.affiliation: INSERM U728 and Department of Medical Oncology, Beaujon University Hospital (AP-HP Paris 7 Diderot), Clichy, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Neuzillet
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.forename: Annemilaï
authors.initials: A
authors.lastname: Tijeras-Raballand
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)