K-ras Inhibitors and Pancreatic Cancer

Abstract

The ras family includes a group of five guanosine triphosphate-binding proteins (H-ras, K-ras, M-ras, N-ras, and R-ras). In mammals ras-proto-oncogenes encode for four related and highly conserved proteins, H-ras, N-ras, K-ras 4A, and K-ras 4B ( 1 ). Ras proteins serve as important components of signaling pathways involved in a variety of cellular functions, including cell cycle control, cell adhesion, endocytosis, exocytosis, and apoptosis. In order for these proteins to perform their functions they need to bind guanosine triphosphate (GTP) ( 2 ). Guanosine triphosphate creates a conformational change allowing ras to attach more tightly to its intended target. Hydrolysis of GTP to guanosine diphosphate (GDP) inactivates ras. The ability of ras to exchange GDP for GTP is under the control of guanine nucleotide exchange factors (GEFs). The GEFs are activated by growth factors or cytokines and promote the release of GDP and therefore the binding of GTP. GTPase-activating proteins (GAPs) return ras to its inactive state. Although a variety of genetic modifications have been identified in pancreatic carcinoma, mutations of K-ras are by far the most commonly occurring mutation. Mutations are seen in >85% of pancreatic ductal carcinomas ( 3 ). The development of mutations in K-ras appear early in the development of pancreatic cancer, having been observed in precursor lesions within the pancreatic duct ( 4 ). The mutations in K-ras in pancreatic cancer are also unique in that it typically involves codon 12, but may also rarely involve codons 13 or 61 ( 5 , 6 ). These mutations in K-ras make it resistant to GAP and as a result lead to constitutive activation of downstream pathways, resulting in altered regulation of cellular proliferation. In preclinical studies, using the pancreatic cancer cell lines Panc-1 and MiaPaca-2, blocking activated K-ras resulted in increased apoptosis and loss of other malignant features supporting a pivotal role for K-ras in the development and maintenance the malignant phenotype. Based on the frequency and apparent critical role of K-ras in pancreatic cancer several approaches have been developed to block activated K-ras. This includes both farnesyl transferase inhibitors and antisense oligonucleotides.