Yuan Jiang-Xia, Hao Yue, Dai Xian-Zi, Hong Jiao-Jiao, Chen Cheng-Yu, Huo Zheng-Xing, Zhu Jia, Wang Qian
Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.
Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Transl Lung Cancer Res. 2025 Jul 31;14(7):2799-2820. doi: 10.21037/tlcr-2025-164. Epub 2025 Jul 15.
Kirsten rat sarcoma viral oncogene homolog () mutations are one of the most common oncogenic driver mutations in non-small cell lung cancer (NSCLC), with the KRAS G12C mutation being the most common prevalent subvariant. The review aims to explore optimal diagnostic and therapeutic strategies for mutant NSCLC, and to provide guidance for the development of precise treatment approaches for affected.
A comprehensive search was conducted in PubMed, Embase, Web of Science, MEDLINE, the Cochrane Library, and major international conferences proceedings for all English-language publications available up to December 31, 2024. Relevant studies were systematically reviewed, analyzed, and synthesized to inform this review.
In this review, we explore the mutation and its associated signaling pathways, detection techniques, recent advancements in drug development and mechanisms of therapeutic resistance. The mutation was once considered "undruggable" until the breakthrough approval of two targeted inhibitors: AMG510 (sotorasib) and MRTX849 (adagrasib). In China, IBI351 and D-1553 have also been approved for the treatment of adult patients with advanced NSCLC harboring the mutation. Although currently approved only as second-line therapies for metastatic disease, these inhibitors-along with ongoing development of additional -targeted agents-are significantly advancing our understanding of -driven tumor biology. Notably, recent findings indicate that combining dual immune checkpoint inhibitors (ICIs; durvalumab and tremelimumab) with chemotherapy (CT) in patients with advanced NSCLC, including those with KRAS mutations, can result in durable survival benefits. This approach is emerging as a promising first-line treatment strategy.
The landscape of -mutant NSCLC has undergone substantial progress, marked by the successive approval of multiple inhibitors and the development of novel targeted therapies. Moreover, the POSEIDON trial has highlighted the potential of dual ICI therapy combined with CT to achieve sustained clinical benefits. Despite these advances, the heterogeneity of tumor responses underscores the need for further investigation into intrinsic resistance mechanisms and the strategic optimization of combination therapies to enhance treatment outcomes.
Kirsten大鼠肉瘤病毒致癌基因同源物（KRAS）突变是非小细胞肺癌（NSCLC）中最常见的致癌驱动突变之一，其中KRAS G12C突变是最常见的流行亚型。本综述旨在探索KRAS突变型NSCLC的最佳诊断和治疗策略，并为受影响患者精准治疗方法的发展提供指导。
在PubMed、Embase、Web of Science、MEDLINE、Cochrane图书馆以及主要国际会议论文集中进行全面检索，以获取截至2024年12月31日的所有英文出版物。对相关研究进行系统回顾、分析和综合，以为本综述提供信息。
在本综述中，我们探讨了KRAS突变及其相关信号通路、检测技术、药物研发的最新进展以及治疗耐药机制。在两种靶向抑制剂AMG510（索托拉西布）和MRTX849（阿达格拉西布）获得突破性批准之前，KRAS突变曾被认为“不可成药”。在中国，IBI351和D-1553也已获批用于治疗携带KRAS突变的晚期NSCLC成年患者。尽管目前仅被批准作为转移性疾病的二线治疗药物，但这些抑制剂以及其他KRAS靶向药物的不断研发，正在显著推进我们对KRAS驱动的肿瘤生物学的理解。值得注意的是，最近的研究结果表明，在晚期NSCLC患者（包括KRAS突变患者）中，将双重免疫检查点抑制剂（ICIs；度伐利尤单抗和曲美木单抗）与化疗（CT）联合使用，可带来持久的生存益处。这种方法正在成为一种有前景的一线治疗策略。
KRAS突变型NSCLC的格局已取得实质性进展，其标志是多种KRAS抑制剂的相继获批和新型靶向疗法的发展。此外，POSEIDON试验突出了双重ICI疗法联合CT实现持续临床获益的潜力。尽管取得了这些进展，但肿瘤反应的异质性强调了需要进一步研究内在耐药机制，并对联合疗法进行战略优化以提高治疗效果。
