KRAS: Reasons for optimism in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• KRAS mutations are frequent gain-of-function alterations in human cancers.
• Targeting KRAS mutant cancers has historically yielded limited success, with notable failures in clinical trials for non-small cell lung cancer (NSCLC).

Purpose of the Study:

• To review past failures in targeting KRAS mutant disease.
• To highlight emerging strategies for targeting specific KRAS mutations in NSCLC based on lessons learned.

Main Methods:

• Narrative review of historical and contemporary clinical trial data.
• Analysis of the relevance of KRAS mutational subtypes.

Main Results:

• Previous attempts targeting KRAS broadly, including farnesyl transferase inhibition and synthetic lethality approaches, have largely disappointed.
• Focusing on specific KRAS mutational subtypes, such as KRAS G12C, is more promising than a general 'KRAS mutation present' approach.

Conclusions:

• Knowledge from past failures provides a foundation for future advancements in NSCLC treatment.
• Direct small molecule inhibitors targeting specific KRAS subtypes show promising preclinical activity and are advancing towards clinical validation.