RAS-targeted therapies: is the undruggable drugged?

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS proteins (KRAS, NRAS, HRAS) are the most frequently mutated gene family in human cancers.
• For over 30 years, developing effective RAS inhibitors was challenging, with RAS often considered 'undruggable'.
• Recent success with allele-specific covalent inhibitors targeting KRAS G12C in non-small-cell lung cancer marks a significant breakthrough.

Purpose of the Study:

• To review recent advances in therapies targeting mutant RAS proteins.
• To evaluate optimal therapeutic strategies for RAS-driven cancers.
• To discuss future challenges and combination strategies for treating RAS-mutant tumors.

Main Methods:

• Review of current literature on direct RAS inhibitors.
• Analysis of mutation-specific biochemical properties and tissue of origin relevance.
• Exploration of combination therapies including pathway inhibitors, immune checkpoint inhibitors, and T cell-targeting approaches.

Main Results:

• Direct inhibition of mutant RAS via allele-specific inhibitors is currently the most effective therapeutic approach.
• Mutation-specific properties and tumor origin influence treatment effectiveness.
• Combination strategies hold promise for enhancing efficacy against RAS-mutant tumors.

Conclusions:

• Targeting mutant RAS proteins has transitioned from elusive to achievable.
• Combination therapies integrating direct RAS inhibition with other modalities are crucial for future treatment strategies.
• Further research is needed to overcome challenges and optimize treatment for RAS-driven cancers.