Systematic and precise interventions for KRAS-mutant cancers.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS mutations are prevalent oncogenic drivers in human cancers, initiating and progressing solid tumors.
• The development of covalent KRAS^G12C inhibitors has spurred interest in allele-directed therapies and KRAS signaling pathway regulation.

Purpose of the Study:

• To review recent advancements in understanding KRAS structure, conformations, and heterogeneity.
• To summarize direct and indirect therapeutic strategies targeting KRAS mutations.
• To analyze resistance mechanisms and outline counterstrategies for durable cancer treatment.

Main Methods:

• Literature review of KRAS structure, signaling pathways, and therapeutic interventions.
• Analysis of allele-specific and conformation-selective inhibitors for KRAS mutations (G12C, G12D, G12V).
• Evaluation of indirect targeting strategies including SHP2/SOS1 inhibition, MEK blockade, metabolic targeting, and immunotherapy combinations.

Main Results:

• Progress in developing allele-specific drugs for KRAS G12C, G12D, and G12V mutations.
• Identification of conformation-selective broad-spectrum inhibitors.
• Analysis of resistance mechanisms and potential counterstrategies like next-generation inhibitors and ctDNA monitoring.

Conclusions:

• The KRAS therapeutic landscape is evolving towards conformation-aware, multimodal precision therapy.
• Longitudinal disease management strategies are crucial for durable control of KRAS-mutant tumors.
• Advances offer new avenues for treating various solid tumors driven by KRAS mutations.