Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS oncogene mutations are prevalent in ~30% of human cancers, driving tumor growth and metastasis via aberrant signaling.
• Historically, RAS proteins were considered
• undruggable
• due to challenges in developing effective small molecule inhibitors.
• While KRAS(G12C)-specific inhibitors like sotorasib represent progress, their utility is limited to a subset of patients and susceptible to resistance mechanisms.

Purpose of the Study:

• To review past and current strategies for developing pan-RAS inhibitors.
• To outline the potential of targeting all RAS isozymes simultaneously.
• To address limitations of allele-specific RAS inhibition.

Main Methods:

• Review of scientific literature on RAS inhibitors.
• Analysis of resistance mechanisms to allele-specific therapies.
• Exploration of pan-RAS inhibition as a therapeutic strategy.

Main Results:

• KRAS(G12C) inhibitors show efficacy but have limited patient populations and resistance issues.
• Wild-type NRAS and HRAS can compensate for KRAS(G12C) inhibition, leading to treatment failure.
• Pan-RAS inhibition aims to target all co-expressed RAS isozymes to overcome these limitations.

Conclusions:

• Developing pan-RAS inhibitors is a crucial alternative strategy to overcome resistance and expand therapeutic options for cancers driven by RAS mutations.
• Targeting all RAS isozymes offers a broader approach than allele-specific inhibitors.
• Pan-RAS inhibition holds promise for treating a wider range of RAS-driven malignancies.