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RASpecting the oncogene: New pathways to therapeutic advances
Matthew C Stout1, Paul M Campbell2
1Department of Pharmacology and Physiology, College of Medicine, Drexel University, USA; Cancer Biology Program and The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, USA.
Biochemical Pharmacology
|October 24, 2018
Summary
RAS proteins are key drivers in many cancers. New research offers novel therapeutic strategies targeting RAS signaling pathways, overcoming previous challenges in developing effective cancer drugs.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS proteins are crucial signaling nodes in cell biology, frequently mutated in approximately 30% of human cancers.
- RAS-driven cancers, including pancreatic and colon cancers, exhibit high frequencies of RAS mutation or overactivation.
- Despite its significance, RAS has historically been a challenging therapeutic target, often referred to as "undruggable" due to failed drug development efforts.
Purpose of the Study:
- To review the recent advancements in developing novel therapeutics targeting RAS signaling.
- To discuss the diverse strategies employed in targeting RAS, including direct activation inhibition, downstream effector blockade, and post-translational modification interference.
- To evaluate the preclinical and early-phase clinical trial outcomes of these emerging RAS-targeted drugs.
Main Methods:
- Review of current scientific literature on RAS biology and targeted therapies.
- Analysis of preclinical data and early-phase clinical trial results for novel RAS-targeting agents.
- Categorization of therapeutic approaches based on their mechanism of action against RAS signaling.
Main Results:
- A resurgence in RAS-targeted drug development is evident, driven by increased understanding of RAS biology.
- Novel therapeutics employ distinct strategies: direct RAS inhibition, downstream effector blockade, and interference with RAS post-translational processing and trafficking.
- Early clinical trials show promise for some of these novel agents, indicating a potential shift in treating RAS-driven cancers.
Conclusions:
- Recent breakthroughs in understanding RAS biology have revitalized the development of targeted cancer therapies.
- Novel therapeutic strategies are showing potential in overcoming the historical challenges of targeting RAS.
- These emerging drugs represent a promising new avenue for treating a significant proportion of human cancers driven by RAS mutations.
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