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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.
Abstract:
RAS is the most commonly mutated driver of tumorigenesis, seen in about 30% of all cancer cases. There is a subset of tumors termed RAS-driven cancers in which RAS mutation or overactivation is evident, including as much as 95% in pancreatic and 50% in colon cancer. RAS is a family of small membrane bound GTPases that act as a signaling node to control both normal and cancer biology. Since the discovery of RAS' overall prominence in many tumor types and specifically in RAS-dependent cancers, it has been an obvious therapeutic target for drug development. However, RAS has proved a very elusive target, and after a few prominent RAS targeted drugs failed in clinical trials after decades of research, RAS was termed "undruggable" and research in this field was greatly hampered. An increase in knowledge about basic RAS biology has led to a resurgence in the generation of novel therapeutics targeting RAS signaling utilizing various and distinct approaches. These new drugs target RAS activation directly, block downstream signaling effectors and inhibit proper post-translational processing and trafficking/recycling of RAS. This review will cover how these new drugs were developed and how they have fared in preclinical and early phase clinical trials.
Insights
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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