Cancer Cell：新型siRNA，选择性靶向抑制肿瘤KRAS G12V突变

Core Viewpoint - The article discusses the significance of KRAS gene mutations in cancer, particularly focusing on the development of a first-in-class siRNA drug targeting the KRAS G12V mutation, which currently lacks approved inhibitors [2][4][6]. Group 1: KRAS Gene Mutations - KRAS gene mutations are present in nearly 25% of human cancers, with high prevalence in lung cancer (35%), colorectal cancer (49%), and pancreatic adenocarcinoma (92%) [2]. - The most common KRAS mutations include KRAS G12D (29%), KRAS G12V (23%), and KRAS G12C (15%) [2]. - Historically, KRAS has been considered a challenging drug target, but recent approvals of small molecule inhibitors for KRAS G12C indicate a need for more specific inhibitors targeting other KRAS mutations [2]. Group 2: Development of EFTX-G12V - A new EGFR-directed siRNA drug, EFTX-G12V, has been developed to selectively target the KRAS G12V mutation, which is the second most common KRAS mutation in cancer [4][6]. - The research team utilized an EGFR-binding peptide to enhance the specificity of the siRNA for cancer cells, demonstrating superior anti-tumor activity compared to pan-KRAS siRNA [10]. - EFTX-G12V effectively silenced KRAS G12V in various cancer models, showing significant tumor growth inhibition in lung, colon, and pancreatic cancer models [10]. Group 3: Implications and Future Prospects - The technology behind EFTX-G12V is highly modular, allowing for the potential targeting of nearly any oncogene by simply replacing the siRNA sequence [9]. - This dual-action approach may help overcome drug resistance and enhance the durability of treatment effects [9]. - Overall, this research represents a significant advancement in RNAi-based siRNA drugs for targeting oncogenic mutations, providing new biological insights for KRAS-targeted therapies with broader clinical implications [12].