Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Feb:54:121-130.
doi: 10.1016/j.semcancer.2017.11.021. Epub 2017 Dec 2.

Concepts and advances in cancer therapeutic vulnerabilities in RAS membrane targeting

James V Michael  1 , Lawrence E Goldfinger  2
Affiliations
Review

Concepts and advances in cancer therapeutic vulnerabilities in RAS membrane targeting

James V Michael et al. Semin Cancer Biol. 2019 Feb.

Abstract

For decades oncogenic RAS proteins were considered undruggable due to a lack of accessible binding pockets on the protein surfaces. Seminal early research in RAS biology uncovered the basic paradigm of post-translational isoprenylation of RAS polypeptides, typically with covalent attachment of a farnesyl group, leading to isoprenyl-mediated RAS anchorage at the plasma membrane and signal initiation at those sites. However, the failure of farnesyltransferase inhibitors to translate to the clinic stymied anti-RAS therapy development. Over the past ten years, a more complete picture has emerged of RAS protein maturation, intracellular trafficking, and location, positioning and retention in subdomains at the plasma membrane, with a corresponding expansion in our understanding of how these properties of RAS contribute to signal outputs. Each of these aspects of RAS regulation presents a potential vulnerability in RAS function that may be exploited for therapeutic targeting, and inhibitors have been identified or developed that interfere with RAS for nearly all of them. This review will summarize current understanding of RAS membrane targeting with a focus on highlighting development and outcomes of inhibitors at each step.

Keywords: Galectin; Lipid rafts; Plasma membrane; RAS; Therapeutics.

PubMed Disclaimer

Conflict of interest statement

6. Conflict of Interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. RAS protein maturation processes and inhibitors
Posttranslational modifications of RAS polypeptides mediate RAS trafficking through the endoplasmic reticulum and Golgi, and subsequent trafficking to the plasma membrane as described in the text. In the specific case of KRAS4B, chaperone protein PDE6δ (PDE) is critical for cytosolic trafficking; NRAS appears to be chaperoned by VPS35 binding to its farnesyl group. Small molecule inhibitors discussed in the text are shown for each step in RAS membrane targeting.
Figure 2
Figure 2. RAS signaling and tumorigenesis in response to inhibition of Galectins and mTOR
a) HRAS-GAL1 and KRAS-GAL3 coupling support downstream RAS oncogenic signaling. b) Schematic of predicted effects of anti-Galectin treatments in H- and KRAS cancers. Galectin-1 inhibition using OTX008 or other GAL1 inhibitors results in loss of HRAS at the lipid ordered/disordered domain borders, and disruption of MAPK mitogenic signaling. GAL3 inhibition with modified citrus pectin, GSC-100, or other inhibitors blocks MAPK signaling by destabilizing KRAS membrane retention. Some PI3K signal output is retained by these treatments. c) Predicted effects of dual inhibition of Galectins and mTOR. Rapamycin or rapalog treatment potently reduces mTOR survival signaling. Combinatorial pathway inhibition blocks MAPK and PI3K signaling by RAS, resulting in an additive anti-tumor effect over either monotherapy.
Figure 3
Figure 3. Dual inhibition of mTOR and Gal3 in Kras mutant LLC tumor growth and Ras signaling
a) Genomic sequencing of exon1 of Kras in LLC cells using flanking primers revealed a G->T SNP resulting in G12C codon substitution. n = 3, sequenced both forward and reverse. b) LLC allograft tumor growth in C57Bl/6 mice. Mice were shaved and injected i.p. with 5 mg/kg rapamycin, and/or 100 mg/kg MCP, or vehicle as indicated, every 48 hours beginning at day 0 of tumor implantation in the flanks. Tumor volumes were measured with calipers. *, p < 0.03. **, p < 0.001. #, p < 0.05. n = 10. c) Ras pathway signaling in LLC tumor lysates after mono or dual drug treatment. Resected tumors from (b) were lysed and proteins blotted for total Erk, total S6, phospho-Erk (pERK), and phospho-S6 (pS6) as indicated. Veh, vehicle; Rap, rapamycin; MCP, modified citrus pectin. Blots representative of 4 independent experiments.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22. - PubMed
    1. Johnson L, et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 1997;11:2468–2481. - PMC - PubMed
    1. Fernandez-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011;2:344–358. - PMC - PubMed
    1. Adjei A. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst. 2001;93:1062–1074. - PubMed
    1. Fernández-Medarde A, Santos E. Ras in Cancer and Developmental Diseases. Genes and Cancer. 2011;2:344–359. - PMC - PubMed

Publication types

MeSH terms