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Ras signaling pathway proteins as therapeutic targets
1Mayo Clinic, Division of Medical Oncology, 200 First Street S.W., Rochester, MN 55905, USA. adjei.alex@mayo.edu
Abstract:
Ras is a 21 kDa membrane-localized G protein that is coupled to receptor and non-receptor tyrosine kinase activation of downstream cytoplasmic and nuclear events. Mutated ras genes are common, and occur in a wide variety of human malignancies. These activating mutations result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis. Preclinically, inhibitors of ras signaling revert ras-dependent cellular transformation, and cause regression of ras-dependent rodent tumor xenografts. The ras signaling pathway has therefore attracted considerable attention as a target for anticancer therapy. In this review, novel therapeutic approaches based on the inhibition of ras-mediated signaling, are described. The discussion will be limited to inhibitors which are currently in human clinical trials, and include inhibitors of ras processing, inhibitors of ras protein synthesis and inhibitors of downstream ras effectors.
Insights
Targeting mutated Ras proteins, common in human cancers, offers new anticancer therapies. This review covers inhibitors of Ras processing, synthesis, and downstream effectors currently in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ras proteins are key G proteins regulating cell signaling pathways.
- Mutated Ras genes are prevalent in numerous human cancers, leading to uncontrolled cell growth.
- Constitutive Ras signaling promotes proliferation and inhibits apoptosis, driving malignancy.
Purpose of the Study:
- To review novel therapeutic strategies targeting the Ras signaling pathway.
- To focus on inhibitors currently undergoing human clinical trials.
- To discuss inhibitors targeting Ras processing, protein synthesis, and downstream effectors.
Main Methods:
- Literature review of preclinical and clinical studies.
- Analysis of therapeutic approaches targeting Ras signaling.
- Focus on inhibitors in human clinical trials.
Main Results:
- Ras pathway inhibitors have shown preclinical efficacy in reverting cellular transformation and reducing tumor xenografts.
- Several classes of Ras-targeting inhibitors are progressing through clinical trials.
- Inhibitors target various stages: Ras processing, protein synthesis, and downstream effector pathways.
Conclusions:
- Inhibition of the Ras signaling pathway represents a promising anticancer therapeutic strategy.
- Clinical trials are evaluating novel inhibitors targeting Ras processing, synthesis, and effectors.
- Targeting Ras offers a viable approach for treating Ras-dependent malignancies.