Worldwide, lung cancer is responsible for the highest number of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the most common histological subtype. Among the different mutations in NSCLC, Kirsten rat sarcoma viral oncogene (KRAS) mutations are frequently observed. Unfortunately, patients with NSCLC carrying KRAS mutations typically exhibit a poor response to chemotherapy and have a poor prognosis. However, the emergence of immunotherapy has shown potential to improve the clinical outcomes of patients with KRAS-mutant NSCLC. At present, there are no targeted drugs specifically designed for KRAS-mutant NSCLC. Nevertheless, there are promising clinical trial results for new small-molecule KRAS G12C inhibitors, such as AMG510 and MRTX849, which may potentially treat KRAS-mutant NSCLC. In addition, numerous other targeted drugs are currently in development.
The RAS gene encodes a low molecular weight G protein with guanosine triphosphatase activity that regulates cell growth and differentiation by activating downstream molecules and different signalling pathways. The main pathways include the MAPK pathway and the PI3K-AKT-mTOR pathway, which control cell proliferation and survival. The RAS-like proto-oncogene guanine nucleotide dissociation stimulator pathway primarily stimulates the transcription of genes that promote survival and cell cycle progression. Three genes related to human tumours in the RAS gene family are HRAS, KRAS, and NRAS, with KRAS having the most significant impact on human cancer. Mutations in the KRAS oncogene prevent GTP hydrolysis to GDP and maintain the active state, leading to intracellular cascade reactions and tumourigenesis.
KRAS mutations are a significant contributor to non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma, with a prevalence of over 80% in codon 12. The most common KRAS mutations are KRAS G12C, KRAS G12V, and KRAS G12D, among others. KRAS mutations are mostly associated with smoking habits, and only about 5% of cases occur in light- or non-smokers. Interestingly, non-smokers are more likely to have KRAS G>A transformation mutations, while smokers tend to have G>T translocation mutations. Patients with KRAS-mutant NSCLC have a poorer prognosis, with a shorter median overall survival and a lower two-year survival rate.
NSCLC patients with KRAS mutations have limited treatment options, and chemotherapy is currently the main approach. However, KRAS mutations do not predict chemotherapy response, and patients with KRAS-mutant NSCLC have poorer outcomes, including shorter overall survival, lower disease control rates, and more aggressive disease manifestations. EGFR tyrosine kinase inhibitors have shown poor efficacy in KRAS-mutant NSCLC, and there are currently no targeted therapies approved specifically for KRAS-mutant NSCLC. Thus, new treatment strategies are urgently needed for this patient population.
The lack of a suitable “pocket” for small-molecule binding and the strong affinity of KRAS for GTP and GDP pose a challenge for developing drugs that selectively target mutant KRAS while sparing the normal KRAS protein. Additionally, the high homology of KRAS with other RAS proteins, with nearly 90% similarity in the G or catalytic domain sequences, further complicates the development of selective drugs (32). Thus, developing effective treatments for KRAS-mutant cancers remains a significant challenge in oncology.
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