مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
KRAS-G12C Inhibition in Cancer Therapy: Current Progress and Future Directions
KRAS-G12C Inhibition in Cancer Therapy: Current Progress and Future Directions
Ali Madadi Mahani,1,*
1. Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
Introduction: Cancer is a leading global cause of mortality, driven by a complex interplay of genetic and environmental factors. Among genetic alterations, mutations in proto-oncogenes are major contributors to cancer development and progression. The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in human cancers. Mutations in KRAS, particularly at codon 12, result in constitutive activation of downstream signaling pathways that promote uncontrolled cell proliferation and survival. The G12C mutation is a prominent subtype, especially prevalent in non-small cell lung cancer (NSCLC). Due to its central role in tumorigenesis, KRAS-G12C has emerged as a promising therapeutic target. This review summarizes the biological role of KRAS-G12C in cancer and highlights recent advancements in targeted inhibition strategies.
Methods: A comprehensive literature review was conducted using PubMed, Embase, Scopus, and Web of Science databases to identify relevant studies published up to June 2025. Keywords included "KRAS", "KRAS-G12C", "cancer", and related MeSH terms. Both original research articles and systematic reviews were analyzed to assess KRAS-G12C’s molecular function, its role in oncogenesis, and the development of targeted therapies.
Results: KRAS is a small GTPase that functions as a molecular switch in key signaling pathways, including MAPK and PI3K/AKT. When mutated, KRAS becomes constitutively active, bypassing normal regulatory mechanisms. The KRAS-G12C mutation results from the substitution of glycine with cysteine at position 12, locking the protein in an active GTP-bound state. This mutation is particularly common in NSCLC, but also occurs in colorectal cancer and pancreatic ductal adenocarcinoma. The development of small molecule inhibitors that specifically target KRAS-G12C marked a major milestone in precision oncology. Sotorasib (AMG 510) became the first KRAS-G12C inhibitor approved by the U.S. FDA in 2021 for advanced NSCLC. It works by irreversibly binding to the mutant cysteine residue, trapping KRAS in an inactive GDP-bound state and thereby inhibiting downstream oncogenic signaling. Clinical trials have demonstrated favorable response rates and manageable toxicity profiles in patients with KRAS-G12C-mutant tumors. Despite these advances, the clinical efficacy of KRAS-G12C inhibitors as monotherapy has limitations. Primary and acquired resistance remains a significant hurdle. Resistance mechanisms include secondary KRAS mutations, activation of alternative signaling pathways, and adaptive rewiring of tumor cell signaling networks. As a result, combination therapies are being actively investigated to enhance and prolong therapeutic responses. Agents targeting mTOR, PI3K, EGFR, ERK, and IGF-1R have shown potential synergy with KRAS-G12C inhibitors in preclinical and early-phase clinical studies.
Conclusion: Targeting KRAS-G12C represents a transformative approach in the treatment of cancers harboring this mutation, particularly NSCLC. The approval of Sotorasib has validated the druggability of KRAS, once considered “undruggable.” However, resistance mechanisms and limited long-term efficacy necessitate further research. Combination therapies and next-generation KRAS inhibitors are promising strategies to overcome these challenges. Continued investigation into the molecular underpinnings of resistance and the development of personalized treatment regimens will be essential to fully harness the potential of KRAS-targeted therapies.