Targeting Raf-kinase: molecular rationales and translational issues

Target-based therapy has been a promising anti-cancer strategy in the preclinical setting, but its efficacy is still limited in clinical practice. The latter was probably due to the lack of identification of molecular targets in order to predict clinical response and for the existence of multiple survival compensatory downstream pathways. Therefore, the use of downstream targets could be useful in order to avoid these overcoming pathways. One of these targets is Raf-kinase. In this review we describe the structure and functions of the components of Raf-kinase family and their relevance in proliferation and survival of tumor cells. Moreover, we illustrate the signal transduction pathways regulated by Raf-kinases. The main preclinical and clinical results obtained with the use of the Raf- kinase inhibitor BAY 43- 9006 or sorafenib are also described. The multi-target function of sorafenib is also explained and the disclosure of new therapeutic opportunities based on the dual inhibition of cancer proliferation and neo-angiogenesis is discussed. In conclusion, Raf-kinase appears an appealing therapeutic target, even it other preclinical and clinical studies are warranted in order to evaluate the activity of sorafenib both in monotherapy and in combination with other agents.