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Drugging the undruggable RAS: Mission Possible?

Key Points

  • Attempts to target RAS pharmaceutically have not yet yielded small molecules with sufficient potency and drug-like characteristics to be useful, but additional approaches are underway.

  • Inhibitors of RAS membrane interaction and subcellular localization remain attractive targets for therapeutic intervention. In this regard, recent discoveries of functionally relevant post-translational modifications of RAS, such as phosphorylation and ubiquitylation, suggest new opportunities to block RAS function.

  • Inhibitors of RAS effector signalling are currently centred on the RAF–MEK–ERK and PI3K–AKT–TOR pathways, with many inhibitors of components of these two pathways under clinical evaluation. The less well-studied effector pathways that lead to activation of RAL and RAC small GTPases are also promising targets.

  • Despite some setbacks owing to issues of reproducibility, functional screens for synthetic lethal interactors with oncogenic RAS remain an attractive approach to identify novel drug targets for RAS-driven cancers.

  • RAS-driven cancers become efficient scavengers of nutrients and may rely on pathways such as autophagy and macropinocytosis. Furthermore, oncogenic KRAS has a crucial role in altering tumour metabolism, including rewiring of both glucose- and glutamine-dependent metabolic pathways. These alterations could provide the opportunity for novel therapeutic interventions.

  • Inhibitors of RAS membrane interaction and subcellular localization remain attractive targets for therapeutic intervention. In this regard, recent discoveries of functionally relevant post-translational modifications of RAS, such as phosphorylation and ubiquitylation, suggest new opportunities to block RAS function.

  • RAS-driven cancers become efficient scavengers of nutrients and may rely on pathways such as autophagy and macropinocytosis. Furthermore, oncogenic KRAS has a crucial role in altering tumour metabolism, including rewiring of both glucose- and glutamine-dependent metabolic pathways. These alterations could provide the opportunity for novel therapeutic interventions.

Abstract

Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.

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Figure 1: Approaches to discover and develop pharmacological inhibitors of mutant RAS.
Figure 2: Compounds that have been reported to bind to RAS.
Figure 3: Inhibitors of RAS effector signalling under clinical evaluation.
Figure 4: Three-dimensional structures of RAS–ligand complexes.
Figure 5: Synthetic lethal interactors in RAS-mutant cancers.
Figure 6: RAS-driven alterations in metabolism.

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Acknowledgements

The work of C.J.D. and A.D.C. is supported by US National Institutes of Health (NIH) grants CA042978, CA179193 and CA175747, and by grants from the Lustgarten Foundation for Pancreatic Cancer Research, USA, and the Pancreatic Cancer Action Network-American Association for Cancer Research. The work of S.W.F. is supported by NIH grants DP1OD006933/DP1CA174419 (NIH Director's Pioneer Award; S.W.F.), P50A095103-12 (NCI SPORE in GI Cancer; R. J. Coffey), and RC2CA148375 (NIH ARRA Stimulus Grant; L. J. Marnett), and by the Lustgarten Foundation for Pancreatic Cancer Research. The work of A.C.K. is supported by NIH grant R01CA157490, American Cancer Society Research Scholar Grant RSG-13-298-01-TBG and by the Lustgarten Foundation. A.C.K. is a consultant for Forma Therapeutics. The work of J.L. is supported by the US National Cancer Institute Intramural Program.

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Correspondence to Channing J. Der.

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C.J.D. has received honoraria from Novartis, AstraZeneca and Eli Lilly and grant support from GlaxoSmithKline and Onconova. A.C.K. is a consultant for Forma Therapeutics. A.D.C., S.W.F. and J.L. declare no competing interests.

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Supplementary information

Supplementary information S1 (table)

Cancer gene mutation frequencies (PDF 89 kb)

Supplementary information S2 (table)

Frequency of RAS mutations in human cancers (PDF 531 kb)

Supplementary information S3 (figure)

RAS mutations in human cancer (PDF 153 kb)

Glossary

Undruggable

Druggable biological targets such as some proteins can be bound with high affinity by small molecules, natural products, or antibodies in such a way that the binding then alters target function to achieve a therapeutic benefit. Undruggable targets are not amenable to such interventions.

RNA interference

(RNAi). A method of gene silencing in which short, double-stranded RNA molecules degrade target mRNAs in a sequence-specific manner to inhibit the expression and function of genes of interest.

GTPase

An enzyme that binds and hydrolyzes GTP to GDP. GTP binding and hydrolysis take place within a highly conserved G-domain shared among all GTPases.

Isoprenoid

A class of organic lipid compounds made up of two or more structural units derived from isoprene, a five-carbon hydrocarbon with a branched-chain structure.

Prenylation

The covalent and irreversible addition of hydrophobic 15- or 20-carbon isoprenyl groups to the carboxy-terminus of proteins with an appropriate signal motif. This modification facilitates protein attachment to cell membranes.

NMR

NMR (nuclear magnetic resonance) is the selective absorption of electromagnetic radiation by an atomic nucleus in the presence of a strong, static magnetic field. NMR spectroscopy is often used to determine the structure and dynamics of proteins in solution.

Fragment-based screening

A method in drug discovery used to find lead compounds, based on initial identification of small chemical fragments that may bind only weakly to the biological target. By combining the fragments, a higher affinity lead compound can be designed.

Electrophile

A reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. A nucleophile is a reactant that provides a pair of electrons to form a new covalent bond.

Driver

Driver mutations confer a growth and/or survival advantage on cancer cells; they may or may not be required for maintenance of advanced malignancies. This contrasts with passenger mutations, which do not confer such an advantage and therefore do not contribute to cancer development.

Allosteric regulation

Regulation of an enzyme by binding of a molecule at a site that is not directly involved in its enzymatic activity. This binding often results in a conformational change that then enhances or decreases enzyme activity.

Achilles' heel

A deadly weakness or vulnerable point whose targeting can lead to the downfall of an otherwise strong entity (e.g., protein).

Synthetic lethality

A genetic interaction whereby two otherwise non-lethal genetic mutations lead to cell death.

CRISPR

CRISPR (clustered regularly interspaced short palindromic repeat) is an RNA-guided gene-editing platform that utilizes the bacterial protein Cas9 and a synthetic guide RNA to introduce a double-stranded DNA break at a specific location within the genome.

Autophagy

A cellular mechanism of 'self-eating' in which unneeded or dysfunctional cellular components are degraded by the lysosome and made available for recycling. Autophagy can assist in the stress response and support cellular survival by maintaining cellular energy levels during nutrient deficiency.

Macropinocytosis

An actin-driven mechanism of endocytosis in which large fluid droplets are trapped in a large organelle originating from plasma membrane extensions (ruffles) of the cell surface.

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Cox, A., Fesik, S., Kimmelman, A. et al. Drugging the undruggable RAS: Mission Possible?. Nat Rev Drug Discov 13, 828–851 (2014). https://doi.org/10.1038/nrd4389

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