title: The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting.
abstract: RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives.
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", F-59000, Lille, France. Electronic address: nicolas.jonckheere@inserm.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jonckheere
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", F-59000, Lille, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Vasseur
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", F-59000, Lille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
keywords: Cell signaling; K-RAS; Metabolism reprogramming; Pancreatic cancer; Therapy