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Mimicking the Function of Signaling Proteins: Toward Artificial Signal Transduction Therapy
Published on: September 29, 2016
Ras family signaling: therapeutic targeting
Adrienne D Cox1, Channing J Der
1University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Abstract:
Mutationally activated and oncogenic versions of the ras genes were first identified in human tumors in 1982. This discovery prompted great interest in the development of anti-Ras strategies as novel, target-based approaches for cancer treatment. The three human ras genes represent the most frequently mutated oncogenes in human cancers. Consequently, a considerable research effort has been made to define the function of Ras in normal and neoplastic cells and to target Ras for cancer treatment. Among the anti-Ras strategies that are under evaluation in the clinic are pharmacologic inhibitors designed to prevent: (1) association with the plasma membrane (farnesyltransferase inhibitors), (2) downstream signaling (Raf and MEK protein kinase inhibitors), (3) autocrine growth factor signaling (EGF receptor inhibitors), or (4) gene expression (H-ras and c-raf-1). Although a number of these inhibitors have demonstrated potent anti-tumor activities in preclinical models, phase l-lll clinical trials have revealed unexpected complexities in Ras function and in the clinical development of target-based therapies. We review the current status of anti-Ras drug development, issues that have complicated their progression to the clinic, and possible future strategies for targeting Ras.
Insights
Targeting Ras oncogenes in cancer therapy shows promise, but clinical trials reveal complexities. Future strategies are needed to overcome challenges in developing effective anti-Ras drugs.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ras genes are frequently mutated oncogenes in human cancers, identified in 1982.
- Ras proteins play crucial roles in normal and neoplastic cell functions.
- Targeting Ras is a key strategy for novel cancer treatments.
Purpose of the Study:
- To review the current status of anti-Ras drug development.
- To discuss challenges encountered in clinical trials of Ras-targeted therapies.
- To explore future strategies for effectively targeting Ras in cancer treatment.
Main Methods:
- Review of preclinical and clinical trial data for various anti-Ras strategies.
- Analysis of pharmacologic inhibitors targeting Ras pathways.
- Evaluation of complexities in Ras function and targeted therapy development.
Main Results:
- Several anti-Ras inhibitors targeting different pathways (e.g., farnesyltransferase, Raf/MEK, EGF receptor) show preclinical anti-tumor activity.
- Clinical trials (Phase I-III) have exposed unexpected complexities in Ras biology and targeted therapy efficacy.
- Development of Ras-targeted therapies faces significant hurdles.
Conclusions:
- Despite initial promise, Ras-targeted cancer therapies have encountered clinical development challenges.
- Understanding Ras pathway complexities is crucial for advancing effective anti-Ras drug strategies.
- Further research into novel therapeutic approaches is necessary for successful Ras-targeted cancer treatment.
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