Stopping the beating heart of cancer: KRAS reviewed

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS-driven cancers have lacked targeted therapies for decades.
• Recent advances include identifying druggable KRAS pockets and developing covalent KRAS G12C inhibitors.
• Sotorasib is the first approved therapy for KRAS G12C-mutated non-small cell lung cancer.

Purpose of the Study:

• To review the structure, function, and modifications of KRAS.
• To highlight current and emerging strategies for targeting KRAS mutations.
• To discuss novel molecular modalities and future challenges in KRAS-targeted therapy.

Main Methods:

• Review of scientific literature on KRAS biology and targeted therapies.
• Analysis of structural and functional data of KRAS.
• Discussion of various drug development approaches, including selective and pan-KRAS inhibitors.
• Exploration of molecular modalities like PROTACs and molecular glues.

Main Results:

• Significant progress in targeting KRAS G12C mutations with approved therapies.
• Identification of druggable pockets and development of covalent inhibitors.
• Ongoing research into diverse strategies to address the remaining 85% of KRAS-mutated cancers.

Conclusions:

• The development of KRAS-targeted therapies has entered a new era, with initial successes for specific mutations.
• Further research is crucial to develop novel agents for the majority of KRAS-mutated cancers.
• Addressing resistance mechanisms and exploring new molecular modalities are key for future advancements.