From Ras signalling to ChoK inhibitors: a further advance in anticancer drug design Ana Ramı ´rez de Molina, Agustı ´n Rodrı ´guez-Gonza ´lez, Juan Carlos Lacal * Department of Molecular and Cellular Biology of Cancer, Instituto de Investigaciones Biome ´dicas, CSIC, Arturo Duperier 4, Madrid 28029, Spain Received 21 July 2003; accepted 1 August 2003 Abstract Cancer is a genetic disease, most prominent in developed countries, with still a high mortality rate [1]. Cancer cells are continuously proliferating, and this uncontrolled growth is mediated by the activation of different signal transduction pathways that ultimately lead to the carcinogenic process. Consequently, a large effort has been devoted to design specific molecules that interfere with these signaling cascades involved in tumorigenesis. In the last decades, research has resulted in improvements in both detection and treatment of cancer. However, it is still necessary to develop novel antitumoral therapies that would allow an appropriate treatment for each cancer patient. These novel, tumor- and patient-specific therapies will have a dramatic impact in improving the overall survival rates. Ras is one of the most important oncogenes so far identified in human carcinogenesis. Understanding the regulation of Ras-dependent signalling under normal and oncogenic environments may provide clues for the design of efficient specific antitumor strategies. In this review we will illustrate how the family of Ras GTPases may be a valid model for the development of new cancer therapies. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Carcinogenesis; Signal transduction; Cancer therapy; Ras oncogenes; Raf-1 kinase; Ral-GDP dissociation stimulator; Phosphatidylinositol 3-kinase; Farnesyltransferase inhibitors; Choline kinase inhibitors 1. Ras signalling and the carcinogenic process The Ras family of small GTPases includes three related proteins, Harvey-, Kirsten- (A and B) and N-Ras, that are involved in the regulation of essen- tial cellular functions such as the control of cellu- lar proliferation, development and differentiation, apoptosis, lipid metabolism, cytoarchitecture and membrane trafficking [2,3]. Ras proteins act as key switches in different signal transduction pathways, cycling between an active state, bound to GTP, and an inactive state, bound to GDP [2–5]. Oncogenic forms of Ras are constitutively locked in their active state and transduce signals that mediate cellular prolifer- ation, transformation and tumorigenesis. There are several mechanisms by which Ras proteins can directly participate in the carcinogenic process. Mutations in the ras genes that alters the intrinsic 0304-3835/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2003.08.031 Cancer Letters 206 (2004) 137–148 www.elsevier.com/locate/canlet * Corresponding author. Tel.: þ34-91-585-4420; fax: þ 34-91- 585-4419. E-mail address: jclacal@iib.uam.es (J.C. Lacal).