The path to the clinic: a comprehensive review on direct KRAS^G12C inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The RAS oncogene, discovered in 1982, is the most frequently mutated oncogene in human cancers.
• A 2013 breakthrough identified a switch II pocket on KRAS, enabling direct inhibition of the KRAS G12C mutation.
• Sotorasib (AMG510) was approved in 2021 as the first therapy targeting KRAS oncoproteins in KRAS-mutant cancers.

Purpose of the Study:

• To review the development of novel KRAS inhibitors targeting the KRAS G12C mutation.
• To examine the discovery, structure, and function of RAS oncoproteins.
• To analyze the clinical relevance and cancer epidemiology of the KRAS G12C mutation.

Main Methods:

• Literature review of RAS oncoprotein discovery and function.
• Analysis of KRAS G12C mutation epidemiology in human cancers.
• Review of preclinical data and ongoing clinical trials for direct KRAS G12C inhibitors.

Main Results:

• The discovery of the switch II pocket enabled the development of direct KRAS G12C inhibitors.
• Sotorasib and adagrasib are examples of approved and investigational direct KRAS G12C inhibitors.
• Multiple clinical trials are evaluating the efficacy of these inhibitors in KRAS-mutant cancers.

Conclusions:

• Directly targeting the KRAS G12C mutation represents a significant advancement in cancer therapy.
• Further research and clinical trials are crucial for optimizing the use of KRAS G12C inhibitors.
• These inhibitors offer new hope for patients with KRAS-mutant cancers.