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Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets

Key Points

  • The RAS superfamily of GTPases includes five major subfamilies of monomeric guanine nucleotide binding proteins (RAS, RHO, RAB, RAN and ARF), which possess GDP/GTP-binding and intrinsic GTPase activities that enable them to interconvert between biologically active (GTP-bound) and inactive (GDP-bound) conformations.

  • RAS GTPases undergo extensive post-translational modifications, which facilitate their membrane attachment and determine their subcellular localization and function.

  • GDP/GTP exchange is controlled by a complex regulatory network comprising several classes of proteins including GTPase activating proteins (GAPs), guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs).

  • Mutational activation, gene amplification and genetic rearrangements involving RAS GTPases and their regulatory proteins (RPs) are prevalent in a various human malignancies.

  • Pharmacological strategies targeting the RAS superfamily of GTPases include inhibitors of their post-translational modifications (mevalonate pathway, prenylation and post-prenylation inhibitors) and inhibitors of their RPs — RP inhibitors and RP–RAS GTPase interfacial inhibitors.

  • Several lines of evidence indicate synergistic activity of these agents with conventional chemotherapeutics, radiation therapy and other molecularly targeted agents. These agents demonstrate different specificities towards RAS GTPases, with interfacial inhibitors showing the highest specificity, and the prenylation and post-prenylation inhibitors being the most 'unspecific' , capable of targeting several RAS GTPases.

  • Identification of appropriate pharmacodynamic molecular and radiographic end points that can guide dose escalation and assess responses to treatment represent a major challenge for the development of these agents.

Abstract

The involvement of the RAS superfamily of monomeric GTPases in carcinogenesis is increasingly being appreciated. A complex array of post-translational modifications and a highly sophisticated protein network regulate the spatio-temporal activation of these GTPases. Previous attempts to pharmacologically target this family have focused on the development of farnesyltransferase inhibitors, but the performance of such agents in cancer clinical trials has not been as good as hoped. Here, we review emerging druggable targets and novel therapeutic approaches targeting prenylation and post-prenylation modifications and the functional regulation of GDP/GTP exchange as exciting alternatives for anticancer therapy.

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Figure 1: Biosynthesis of isoprenoids through the mevalonate pathway.
Figure 2: Prenylation and post-prenylation reactions of RAS GTPases.
Figure 3: Prenylation and post-prenylation reactions of RHO and RAB GTPases.
Figure 4: Functional regulation of the RAS superfamily of GTPases.
Figure 5: Possible strategies for targeting post-translational modifications and functional regulation of the RAS superfamily of GTPases.

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Acknowledgements

The authors would like to thank A. Konstantinopoulou for her invaluable help with the figures.

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Correspondence to Athanasios G. Papavassiliou.

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Konstantinopoulos, P., Karamouzis, M. & Papavassiliou, A. Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov 6, 541–555 (2007). https://doi.org/10.1038/nrd2221

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