Targeting the Ras–ERK pathway in pancreatic adenocarcinoma

• Published in: Cancer and metastasis reviews 2013-06, Vol.32 (1-2), p.147-162
• Main Authors: Neuzillet, Cindy, Hammel, Pascal, Tijeras-Raballand, Annemilaï, Couvelard, Anne, Raymond, Eric
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; Extracellular Signal-Regulated MAP Kinases - metabolism; Health aspects; Humans; Non-Thematic Review; Oncology; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins p21(ras) - metabolism; Signal Transduction - drug effects; Tumor proteins
• ISSN: 0167-7659; 1573-7233
• DOI: 10.1007/s10555-012-9396-2

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.