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Drugging the undruggable RAS: Mission possible?
Adrienne D Cox1, Stephen W Fesik2, Alec C Kimmelman3
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Abstract:
Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.
Insights
Targeting RAS oncoproteins, long considered undruggable, shows renewed promise. This review explores five key strategies, including direct inhibition and targeting downstream effectors, offering new hope for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS oncoproteins have been a persistent challenge in cancer therapy for over 30 years.
- The perception of RAS proteins as 'undruggable' has limited therapeutic development.
- Recent advancements offer new hope for developing effective RAS-inhibitory molecules.
Purpose of the Study:
- To review the progress and potential of five key therapeutic approaches targeting RAS.
- To assess the viability of direct RAS inhibition, membrane association blocking, and downstream effector targeting.
- To explore synthetic lethality and metabolic exploitation for mutant RAS therapies.
Main Methods:
- Review of current scientific literature and clinical data on RAS-targeting strategies.
- Analysis of five distinct therapeutic avenues: direct inhibition, membrane association, downstream signaling, synthetic lethality, and metabolic pathways.
- Discussion of the complexities and future perspectives for each approach.
Main Results:
- Direct RAS inhibition and blocking membrane association are areas of active investigation.
- Targeting RAS downstream effector signaling is currently the most promising approach.
- Exploiting synthetic lethal interactors and RAS-mediated metabolic changes presents novel therapeutic opportunities.
Conclusions:
- Despite historical challenges, multiple strategies show promise for targeting RAS oncoproteins.
- Targeting downstream effectors and exploring metabolic vulnerabilities offer significant therapeutic potential.
- Further research is needed to overcome complexities and fully realize the potential of these RAS-targeting approaches.
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