oa EDITORIAL [Hot topic: RAS - A Central Feature in Cancer Targeted Therapy (Guest Editor: Balazs Gyorffy)

The new millennium brought the transition from classical therapy to targeted cancer therapy. Although multiple pathways are involved in cancer initiation and progression, the RAS pathway seems to emerge as particularly important. In their review article entitled “RAS oncogenes: the first 30 years”, Marcos Malumbres and Mariano Barbacid emphasized that RAS genes have always been at the leading edge of research in various disciplines such as tumor virology, molecular oncology and signal transduction biology [1]. The general interest in RAS research is spurred by the fact that RAS genes are the most common targets for oncogenic mutations in human cancer and by the identification of germ-line mutations causing several developmental disorders [2]. The most recent interest in RAS mutations is fuelled by the finding that therapies targeting the epidermal growth factor receptor (EGFR) are only efficient in cancer patients carrying wild-type KRAS genes, while tumors with KRAS mutation are therapy-refractory [3]. While this finding was not too surprising for experts working in the field of signal transduction and RAS tumor biology, the current clinical impact is enormous and RAS mutation diagnostics has entered clinical routine. The various aspects of RAS function in cancers of viral and non-viral origin, the role of RAS proteins as molecular switches in signal transduction, in growth control and development have been covered in many excellent review articles, of which the most recent one is a publication by Karnoub and Weinberg [4]. In bibliometrical terms, the publication intensity on RAS-related topics slowed down somewhat after 1999, but did not reach a plateau or diminish in the years thereafter (Fig. 1). While the publications devoted to the retrovirological aspects of RAS research stayed constantly between 1985 and 2004 and showed a tendency to decrease from 2005 onwards (not shown), there is a growing number of gene expression profiling studies, mostly based on microarray analysis, aiming at assessing RAS pathway-related transcriptional alterations (Fig. 1). In this hot-topic issue, we cover three different aspects of RAS-related targeted therapy. First, predictive markers to EGFR/RAS targeted therapies are evaluated in two different papers. Barton et al. sum up all available biomarkers of resistance found at different levels of the RAS signaling cascade. Timar et al. critically elaborate on the most critically investigated biomarker, on the role of KRAS mutation testing in colorectal cancer. In the second part, three different cancer types are portrayed in detail. Weickhardt et al. focus on colorectal cancer, and evaluate the agents acting through MAPK and PI3K pathways downstream of mutated K-RAS. The signaling via other HER family members, CMET, IGFR and SRC are also rigorously assessed. Whitaker and Neal assess the role of RAS isoforms in prostate cancer progression, as current evidence already supports the role of RAS in activation of androgen receptor in hormone sensitive cells. Lo summarizes the role of the RAS pathway in malignant gliomas and evaluates the efficacy of RAS-targeted therapies. Finally, in the third part we get an exciting in-depth look on some selected topics: RAS signaling is involved in the switch from tumorsuppressive to tumor-promoting functions of the TGF-beta family, a topic discussed by Grusch et al. The first genome-wide search for RAS pathway targets was published in 2000. Since then, a number of studies were performed in human, mouse and rat model systems. Gyorffy and Schafer critically evaluate commonly deregulated target genes and discuss some of the key genes identified. Although oncogenes like RAS usually promote neoplastic transformation, over-expression of mutant RAS results in cellular senescence. Details of the RAS-induced senescence as well as its effects on cancer therapy are discussed by DiMauro and David. In summary, this hot-topic issue covers recent advances in RAS-related carcinogenesis and therapy response as well as the potential role of other members of the RAS signalling cascade.