KRAS-G12D突变非小细胞肺癌的靶向治疗策略：叙述性综述
Targeted therapeutic strategies for KRAS-G12D-mutant non-small cell lung cancer: a narrative review.
作者
作者单位
- First Clinical Medical College, Chongqing Medical University, Chongqing, China.
- Second Clinical Medical College, Chongqing Medical University, Chongqing, China.
- Department of Pulmonary and Critical Care Medicine, Nantong First People's Hospital, Nantong, China.
摘要
中文
Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）-G12D是非小细胞肺癌（NSCLC）中常见的致癌突变，其靶向治疗方法的开发面临重大挑战。KRAS-G12D在生化和信号转导特征上与KRAS-G12C不同，这限制了靶向KRAS-G12C突变药物的使用，在临床中产生了巨大需求。本综述旨在总结KRAS-G12D突变NSCLC治疗的主要进展，重点关注靶向治疗的最新关键进展和新兴临床数据。使用包括PubMed、Web of Science和Google Scholar在内的电子数据库进行了全面文献检索，并辅以参考文献列表和相关文章的手动检索。本综述聚焦于KRAS-G12D靶向治疗和间接调节抑制剂的临床前及临床研究。针对KRAS-G12D的治疗开发进展迅速。多种直接靶向策略，包括等位基因选择性非共价抑制剂、作用于活性鸟苷三磷酸（GTP）状态的RAS（RAS（ON））选择性抑制剂和靶向蛋白降解（TPD）药物，已在临床前和早期临床研究中显示出抑制KRAS-G12D信号通路的可行性。对上游调节因子如son of sevenless homolog 1（SOS1）和含Src同源2结构域蛋白酪氨酸磷酸酶2（SHP2）的间接抑制，以及阻断下游通路，也提供了结合多种方法的重要治疗手段。此外，共突变模式、肿瘤免疫微环境和适应性耐药机制显著影响治疗反应和临床结局。在多样化药物发现平台和基于机制的联合策略推动下，KRAS-G12D靶向治疗正迅速从概念验证过渡到临床应用。这些进展为NSCLC的精准治疗提供了新的机遇。
English
Kirsten rat sarcoma viral oncogene homolog (KRAS)-G12D is a common oncogenic mutation in non-small cell lung cancer (NSCLC) and has posed significant challenges in the development of treatment approaches that specifically target this alteration. KRAS-G12D differs from KRAS-G12C in its biochemical and signal transduction features, which limits the use of drugs targeting the KRAS-G12C mutation, creating substantial demands in clinical contexts. This review sought to summarize the major developments in treatment for KRAS-G12D-mutant NSCLC, with a focus on the recent key advances and emerging clinical data on targeted therapies. A comprehensive literature search was conducted using electronic databases, including PubMed, Web of Science, and Google Scholar, supplemented by manual searching of reference lists and related articles. The review focused on preclinical and clinical research on KRAS-G12D-targeted therapies and indirect regulatory inhibitors. Rapid progress has been made in development of therapies targeting KRAS-G12D. A variety of direct-targeting strategies, including allele-selective non-covalent inhibitors, RAS in the active guanosine triphosphate (GTP) state [RAS (ON)] selective inhibitors, and targeted protein degradation (TPD) agents, have shown the feasibility of inhibiting the KRAS-G12D signaling pathway in preclinical and early clinical studies. The indirect inhibition of upstream regulators, such as son of sevenless homolog 1 (SOS1) and Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2), and the blocking of downstream pathways have also provided important treatments that combine multiple approaches. In addition, co-mutation patterns, the tumor immune microenvironment, and adaptive resistance mechanisms significantly influence therapeutic responses and clinical outcomes. Driven by diverse drug discovery platforms and mechanism-based combination strategies, KRAS-G12D targeting is rapidly transitioning from conceptual validation to clinical application. These advances provide new opportunities for the precision treatment of NSCLC.
分类与指标
- 研究类型
- 综述Meta
- 病种
- 肺癌
- JCR 分区
- Q2
- 影响因子
- 3.4
- 新锐分区
- 3区