title: Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities.
abstract: Mutation of the KRAS oncogene in pancreatic cancer is responsible for permanent activation of the P21 RAS protein and the cascade of signalling pathways. Consequently, multiple cellular processes, such as transformation, proliferation, invasion, and survival are activated. The aim of this review was to present all potential clinical applications of targeting KRAS in terms of diagnosis and management of pancreatic adenocarcinoma. Quantitative polymerase chain reaction technology provides reliable assessment of KRAS mutations, both in tissues and from fine-needle aspiration biopsies. Numerous studies report that the combination of endoscopic ultrasound-guided cytopathology and a KRAS mutation assay can improve the positive and differential diagnosis of pancreatic cancer, differentiating between benign versus malignant solid pancreatic cancer, and reducing false-negative results compared to cytopathology alone. In addition, the presence of a KRAS mutation is frequently associated with a worse prognosis, both in cases of advanced and resected tumours. However, the KRAS mutation assay is not as efficient at predicting a response to both anti-epidermal growth factor receptor treatments and/or chemotherapy. Targeting of KRAS to treat pancreatic adenocarcinoma has been applied at different stages of RAS molecular intracellular processes: at the transcription level with antisense or interference RNA, at the posttranslational level with inhibitors of farnesyl transferase or anti-RAS vaccination peptides, and to target multiple signalling pathways using inhibitors of mitogen-activated protein kinase, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, RAF. Despite some encouraging results at pre-clinical and phase I stages, no significant clinical benefits have been observed. Combinatory approaches with standard chemotherapy will be welcome.
authors.affiliation: Department of Gastroenterology, CHU Toulouse Rangueil, University of Toulouse, Toulouse, France; INSERM UMR 1037, Center for Cancer Research, Institute of Cancer of the University of Toulouse, Toulouse, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bournet
authors.affiliation: Department of Public Health, CHU Pontchaillou, University of Rennes, Rennes, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Buscail
authors.affiliation: Department of Digestive Surgery, CHU Toulouse Rangueil, University of Toulouse, Toulouse, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Muscari
authors.affiliation: INSERM UMR 1037, Center for Cancer Research, Institute of Cancer of the University of Toulouse, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordelier
authors.affiliation: Department of Gastroenterology, CHU Toulouse Rangueil, University of Toulouse, Toulouse, France; INSERM UMR 1037, Center for Cancer Research, Institute of Cancer of the University of Toulouse, Toulouse, France. Electronic address: Buscail.L@chu-toulouse.fr.
authors.forename: Louis
authors.initials: L
authors.lastname: Buscail
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D020022:Genetic Predisposition to Disease; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS mutation; MEK inhibitors; Pancreatic ductal adenocarcinoma; Prognosis; Quantitative PCR; Solid pancreatic masses