Rac1 GTPase in pancreatic cancer

cancer is the fourth leading cause of cancer death in the Western world. It is a disease of insidious progression and high lethality, with a 5 year survival rate of only 6%. In spite of significant advances in pancreatic cancer research, current therapies are ineffective and fail to significantly extend lifespan. Thus, there is an urgent need for novel and improved therapies for this disease. Activating mutations in the K-Ras gene are the earliest and most common genetic alterations detected in pancreatic cancer specimens. Efforts to target K-Ras with small molecule inhibitors have not yet met with success, and an alternative strategy has been to target its downstream effectors. K-Ras has four effectors that play a role in cancer development (Fig. 1): mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-kinase (PI3K) pathway, Ral guanine nucleotide dissociation stimulator (Ral-GDS), and Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase. Efforts to block these effectors have so far been focused on the MAPK and PI3K pathways, mainly because of the availability of drugs to target these pathways. Studies have now highlighted the importance of yet another K-Ras effector, the Rac1 signaling pathway. This pathway, which has not yet been extensively studied, is as critical for PC development as the MAPK and PI3K pathways. Rac1 is an isoprenylated membrane-bound protein that belongs to the Rho family of small GTPases [1]. Like K-Ras and other GTPases, Rac1 can exist in either an inactive GDP-bound state or active GTP-bound form. In its active form, Rac1 interacts with its downstream effectors, activating them in the process. Many of Rac1 effectors are proteins involved in remodeling the actin cytoskeleton and regulation of cell motility and migration, such as the WAVE and Arp2/3 complexes. Other effectors, like the PAK kinases, have been implicated in the regulation of MAPK signaling, survival and proliferation. The level of GTP-bound Rac1 is controlled by the activities of guanine nucleotide exchange factors (GEF), GTPase activating proteins, and guanine dissociation inhibitors. Two of the GEFs responsible for Rac1 activation, Tiam1 and PREX1, are themselves stimulated by the Ras oncogenes (Fig. 1). Rac1 is also activated by the GEF Vav1 (Fig.1), and Vav1 is up-regulated in the majority of pancreatic cancers. While levels of GTP-bound Rac1 Editorial have never been measured in pancreatic cancer specimens, the pathway is generally assumed to be activated in these tumors, at least in part by the presence of activated K-Ras. Recent …