RAS subfamily constitute the gene family most frequently mutated in human cancer: 22%, 8.2% and 3.7% for KRAS, NRAS and HRAS respectively. To these figures must be added those cases in which mutational activation is detected in downstream effectors. Overall, the proportion of human neoplasias harboring oncogenic mutations in RASinduced pathway constituents exceeds 50%. This fraction, significant as is, somewhat undervalues those referring to specific tumors: 99% of pancreatic carcinomas show KRAS mutational activation; 80% of melanomas harbor mutations in RAS-related pathways; while in thyroid cancer this figure reaches 75% of the cases. In addition, a wealth of gain- and loss-of-function genetic approaches using animal and cellular models mechanistically links RAS-induced pathways to cancer initiation, promotion and progression. It is therefore hardly surprising that these biochemical pathways rank among the most scrutinized in search of targets for oncological therapeutic intervention.

The members of the RAS superfamily behave as ''molecular switches'' that fluctuate between inactive and active states, two conformations that depend on the binding of either GDP or GTP, respectively. Based on structural and functional criteria, this superfamily can be subdivided in several groups, including the RAS, RAP and RHO/RAC families. In the active, GTP-bound state, these GTPases bind to a large collection of effector molecules that, in turn, lead to the stimulation of signaling cascades that promote general cellular responses such as cytoskeletal changes, cell cycle progression and cell proliferation and survival, among many others.

The plasticity of RAS superfamily members in terms of subcellular localization, regulation, binding to effectors, and crosstalk with other cellular pathways has put them in a central regulatory point for a quite large number of cellular processes. Unfortunately, the toll that we have to pay for such important functions in vivo is the development of diseases when these routes become dysfunctional. Indeed, activating mutations of RAS or of components of its effector pathways are common in human cancers, with special incidence in some of the most aggressive tumors for which there are no efficacious treatments. Tumor types frequently harboring RAS oncogenes include pancreatic ductal adenocarcinoma (PDAC) one of the deadliest human cancer; non-small cell lung carcinoma, a tumor type for which the five year survival is less than 10%; and metastatic melanoma, with a survival rate of about 5%, among others.

Not surprisingly, for more than two decades, this has led to a colossal, comprehensive and multidimensional scrutiny of RAS-mediated signaling pathways. In order to understand how these signals impinge on the different biological processes involved in carcinogenesis, with the aim of finding molecular targets for the potential development of therapeutic agents whereby aberrant RAS signals, and, subsequently, tumor progression, could be inhibited.

With the perspective provided by more than thirty years of progress in the field, we are now in an excellent position to review the state-of-the-art of some of these developments, the challenges that have arisen during preclinical and clinical stages and how novel venues of research on the RAS field make conceivable new strategies towards the development of antitumor agents, alternative or complementary, to those currently in use and, for the first time in the history of biomedicine, the design of new therapies based on the specific blockage of molecular targets of RAS superfamilydependent routes. Some of these new therapeutic approaches have been already moved from the bench to the bedside.

In this context, this meeting aims at providing a format for the exchange of ideas and information, to discuss the latest research findings and methodological advances in the RAS-mediated signaling pathways, and to foster interactions amongst groups that investigate these signal transduction pathways at the structural, biochemical, signaling, physiological and/or pathological level. Special topics of attention will be those related to the systems biology of these routes, the analysis of their mechanism of regulation and action, the information derived from animal models, their role in human carcinogenesis, and the new therapeutic avenues that are being developed to manipulate their function.

From other perspective, this meeting will constitute a continuation of the Fundación Ramón Areces-sponsored meeting "Antitumoral targets upstream and downstream of RAS GTPases" held in the same venue in 2012 and remembered in the field as a highly successful gathering.

There will be no poster sessions, but a few slots for short talks will be available to present outstanding data. If you wish to be considered for one of these, please send a 200-250 abstract to: crespop@unican.es