The complex journey of targeting RAS in oncology.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS mutations are prevalent in various cancers, necessitating personalized therapeutic strategies.
• Farnesyltransferase inhibitors (FTIs) show potential but face toxicity and efficacy limitations.
• Targeting RAS is complicated by its structural nuances, particularly in the G domain.

Purpose of the Study:

• To review the challenges and advancements in targeting RAS oncogenes for cancer therapy.
• To discuss emerging therapeutic strategies and their clinical implications.
• To highlight the complexity of RAS-RAF-ERK pathway inhibition and resistance mechanisms.

Main Methods:

• Review of current literature on RAS-targeted therapies.
• Analysis of clinical trial data for RAS inhibitors.
• Exploration of novel drug development and gene-editing technologies.

Main Results:

• Development of targeted therapeutics like sotorasib and adagrasib for KRAS G12C-mutated NSCLC.
• Identification of druggable pockets, such as the SW-II pocket, advancing RAS targeting.
• Emergence of new inhibitors (e.g., LY3537982, GDC-6036) but challenges in selectivity and efficacy persist.

Conclusions:

• Effective RAS inhibition is hindered by adaptive resistance, isoform selectivity issues, and off-target effects.
• Understanding the complex role of RAS in oncogenesis, including context-dependent effects, is crucial.
• Overcoming delivery issues and resistance mechanisms is key for successful RAS-targeted cancer therapies.