Luo Xiyuan, Zhou Feihan, Tang Yuemeng, Liu Xiaohong, Xiao Ruilin, Gu Minzhi, Bai Jialu, Jiang Decheng, Yang Gang, You Lei, Zhao Yupei
Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100023, China.
Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing 100023, China.
Chin Med J (Engl). 2025 Sep 20;138(18):2243-2267. doi: 10.1097/CM9.0000000000003776. Epub 2025 Aug 18.
The Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation is one of the most prevalent activating alterations in cancer. It indicates a poor overall prognosis due to its highly invasive nature. Although several KRAS inhibitors have been developed in recent years, a significant clinical challenge has emerged as a substantial proportion of patients eventually develop resistance to these therapies. Therefore, identifying determinants of drug resistance is critical for guiding treatment strategies. This review provides a comprehensive overview of the mutation landscape and molecular mechanisms of KRAS activity in various cancers. Meanwhile, it summaries the progress and prospects of small molecule KRAS inhibitors undergoing clinical trials. Furthemore, this review explores potential strategies to overcome drug resistance, with the ultimate goal of steering toward patient-centric precision oncology in the foreseeable future.
Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变是癌症中最常见的激活改变之一。由于其高度侵袭性，它预示着总体预后不良。尽管近年来已开发出几种KRAS抑制剂，但由于相当一部分患者最终会对这些治疗产生耐药性，因此出现了一个重大的临床挑战。因此，确定耐药性的决定因素对于指导治疗策略至关重要。本综述全面概述了各种癌症中KRAS活性的突变情况和分子机制。同时，总结了正在进行临床试验的小分子KRAS抑制剂的进展和前景。此外，本综述探讨了克服耐药性的潜在策略，最终目标是在可预见的未来转向以患者为中心的精准肿瘤学。
