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40 Years of RAS-A Historic Overview - PubMed

  • ️Fri Jan 01 2021

Review

40 Years of RAS-A Historic Overview

Alberto Fernández-Medarde et al. Genes (Basel). 2021.

Abstract

It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led to a quantitative leap in our understanding of cancer biology and set up the onset of the field of molecular oncology. The following four decades of RAS research have produced a huge pool of new knowledge about the RAS family of small GTPases, including how they regulate signaling pathways controlling many cellular physiological processes, or how oncogenic mutations trigger pathological conditions, including developmental syndromes or many cancer types. However, despite the extensive body of available basic knowledge, specific effective treatments for RAS-driven cancers are still lacking. Hopefully, recent advances involving the discovery of novel pockets on the RAS surface as well as highly specific small-molecule inhibitors able to block its interaction with effectors and/or activators may lead to the development of new, effective treatments for cancer. This review intends to provide a quick, summarized historical overview of the main milestones in RAS research spanning from the initial discovery of the viral RAS oncogenes in rodent tumors to the latest attempts at targeting RAS oncogenes in various human cancers.

Keywords: GTPases; RAS; cancer; history; milestones.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Milestones in RAS research. Summarized timeline of some key discoveries in RAS research over the last 40 years. We apologize for many key discoveries that could not be included here due to lack of space. The individual boxes point to the year of publication of some selected research advances that significantly contributed to the path leading to our current understanding of RAS structure, function and biology.

Figure 2
Figure 2

The RAS superfamily. Protein phylogenetic tree, including 150 human small GTPases corresponding to distinct, protein-coding gene loci (proteins annotated in the UniProt database). The HRAS sequence was used as the root for tree construction based on the distance matrix derived from the multiple alignment of the 150 amino-acid sequences using the neighbor joining method [33]. The tree includes 36 members of the RAS family (blue), 20 members of the RHO/RAC family (purple), 26 of the ARF family (brown), 60 of the RAB family (green) and 1 of the RAN family (red). Seven proteins that are frequently unclassified are identified here (pointed by arrows in the figure) as RHO-like (2), ARF-like (2) and RAB-like (3).

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