Therapeutic targeting of RAS: New hope for drugging the “undruggable”

RAS is the most frequently mutated oncogene in cancer and a critical driver of oncogenesis. Therapeutic targeting of RAS has been a goal of cancer research for more than 30 years due to its essential role in tumor formation and maintenance. Yet the quest to inhibit this challenging foe has been elus...

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Bibliographic Details
Published in:Biochimica et biophysica acta. Molecular cell research 2020-02, Vol.1867 (2), p.118570-118570, Article 118570
Main Authors: Khan, Imran, Rhett, J. Matthew, O'Bryan, John P.
Format: Article
Language:English
Subjects:
Allosteric Regulation
Alternative Splicing
Antibodies, Monoclonal - immunology
Cancer
Drug discovery
GTPase
Humans
Monobody
Mutation
Neoplasms - metabolism
Neoplasms - pathology
Protein Processing, Post-Translational
RAS inhibitor
ras Proteins - antagonists & inhibitors
ras Proteins - immunology
ras Proteins - metabolism
Signal transduction
Small Molecule Libraries - chemistry
Small Molecule Libraries - metabolism
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Summary:RAS is the most frequently mutated oncogene in cancer and a critical driver of oncogenesis. Therapeutic targeting of RAS has been a goal of cancer research for more than 30 years due to its essential role in tumor formation and maintenance. Yet the quest to inhibit this challenging foe has been elusive. Although once considered “undruggable”, the struggle to directly inhibit RAS has seen recent success with the development of pharmacological agents that specifically target the KRAS(G12C) mutant protein, which include the first direct RAS inhibitor to gain entry to clinical trials. However, the limited applicability of these inhibitors to G12C-mutant tumors demands further efforts to identify more broadly efficacious RAS inhibitors. Understanding allosteric influences on RAS may open new avenues to inhibit RAS. Here, we provide a brief overview of RAS biology and biochemistry, discuss the allosteric regulation of RAS, and summarize the various approaches to develop RAS inhibitors. •RAS mutations occur in nearly early 30% of human tumors.•Different RAS mutations result in context-dependent effects.•Indirect inhibitors of RAS target various aspects of RAS processing.•Direct inhibitors interfere with RAS activation and effector binding.•Newer biologics target RAS activation, effector binding, and self-association.
ISSN:0167-4889
1879-2596
DOI:10.1016/j.bbamcr.2019.118570