Drugging KRAS: current perspectives and state-of-art review

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS is the most frequently mutated oncogene in human malignancies, acting as a critical regulator of cell signaling.
• Mutant KRAS is constitutively active, driving persistent downstream signaling and oncogenesis.
• Targeting KRAS has been a long-standing challenge in cancer therapy, often referred to as the 'holy grail'.

Purpose of the Study:

• To review the discovery, biology, and function of KRAS in human malignancies.
• To explore the relationship between KRAS mutations and the tumor microenvironment.
• To discuss current and emerging therapeutic strategies targeting KRAS, including clinical evidence and resistance pathways.

Main Methods:

• Literature review of KRAS biology, mutation targeting, and therapeutic strategies.
• Analysis of recent advancements in drug design and covalent inhibitor development.
• Examination of clinical trial data and research on resistance mechanisms.

Main Results:

• Significant progress has been made in targeting KRAS mutations, particularly KRAS G12C, with approved drugs like sotorasib.
• The discovery of a specific binding pocket in GDP-bound KRAS G12C enabled the development of covalent inhibitors.
• KRAS mutations influence the tumor microenvironment, impacting treatment responses, especially with immune checkpoint inhibitors.

Conclusions:

• Targeting KRAS mutations, especially KRAS G12C, represents a major breakthrough in cancer therapy.
• Understanding KRAS-tumor microenvironment interactions is crucial for developing effective treatment strategies.
• Ongoing research and clinical trials are expanding therapeutic options and addressing resistance mechanisms for KRAS-driven cancers.