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Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies

Yoshihito Kano1

  • 1Department of Medical Oncology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8510, Japan.

International Journal of Molecular Sciences
|July 15, 2026
PubMed

Insights

KRAS mutations drive cancer, but new drugs targeting KRAS G12C offer hope. Research is expanding to overcome resistance and develop broader KRAS-targeted therapies for better cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS is a frequently mutated oncogene in cancer, historically challenging to target therapeutically.
  • Advances in structural biology and pharmacology enabled development of KRAS G12C inhibitors (sotorasib, adagrasib).
  • Resistance mechanisms and tumor heterogeneity limit durability of current KRAS-targeted therapies.

Purpose of the Study:

  • To review the molecular biology and regulation of KRAS signaling.
  • To summarize recent advances in KRAS-targeted therapies, including allele-specific and pan-RAS inhibitors.
  • To discuss resistance mechanisms and emerging precision oncology strategies for KRAS-mutant cancers.

Main Methods:

  • Literature review of KRAS molecular biology, drug development, and resistance mechanisms.
  • Analysis of recent clinical and preclinical data on KRAS inhibitors and combination therapies.
  • Examination of biomarker-driven strategies, including circulating tumor DNA (ctDNA).

Main Results:

  • KRAS G12C inhibitors represent a significant advance in precision oncology.
  • Developing inhibitors for other KRAS mutations (e.g., G12D) and pan-RAS strategies is ongoing.
  • Understanding resistance mechanisms is crucial for improving therapeutic efficacy.

Conclusions:

  • Direct KRAS inhibition is feasible, but overcoming resistance is key for durable responses.
  • Broader therapeutic strategies and combination approaches are essential for treating KRAS-mutant cancers.
  • Biomarker monitoring, including ctDNA, aids in dynamic treatment management and understanding resistance evolution.
Keywords:
KRAS G12CKRAS G12DRAS(ON) inhibitorsliquid biopsypan-RAS targetingprecision oncologytargeted protein degradation

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