Liu Hongyu, Zhou Chao, Lu Jun, Liu Yuqing, Zou Peichen, Zhu Liang, Lei Huimin, Han Baohui
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Dis. 2025 May 2;16(1):356. doi: 10.1038/s41419-025-07687-w.
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, with KRAS mutations present in approximately 20-25% of cases. The KRAS-G12C mutation, occurring in approximately 14% of lung adenocarcinomas, has emerged as a critical target for precision medicine strategies. While KRAS-G12C inhibitors, including sotorasib and adagrasib, have shown promise in clinical trials, their efficacy is limited by primary and acquired resistance mechanisms. This study explored the potential of combining anlotinib, a multi-target tyrosine kinase inhibitor, with KRAS-G12C inhibitors to overcome these resistance challenges in NSCLC treatment. Our results demonstrated that anlotinib improved the sensitivity to KRAS-G12C inhibitors in primary and acquired resistance settings, both in vitro and in vivo. Mechanistically, the combination therapy inhibited c-Myc/ORC2 signaling, leading to cell cycle arrest and apoptosis. These findings suggest that the combination of anlotinib and KRAS-G12C inhibitors represents a promising novel therapeutic approach for KRAS-G12C-mutant NSCLC.
非小细胞肺癌（NSCLC）仍然是全球癌症相关死亡的主要原因，约20%-25%的病例存在KRAS突变。KRAS-G12C突变约发生在14%的肺腺癌中，已成为精准医学策略的关键靶点。虽然包括索托拉西布和阿达格拉西布在内的KRAS-G12C抑制剂在临床试验中显示出前景，但其疗效受到原发性和获得性耐药机制的限制。本研究探索了多靶点酪氨酸激酶抑制剂安罗替尼与KRAS-G12C抑制剂联合使用，以克服NSCLC治疗中这些耐药挑战的潜力。我们的结果表明，安罗替尼在体外和体内均提高了原发性和获得性耐药情况下对KRAS-G12C抑制剂的敏感性。从机制上讲，联合治疗抑制了c-Myc/ORC2信号传导，导致细胞周期停滞和凋亡。这些发现表明，安罗替尼和KRAS-G12C抑制剂联合使用代表了一种有前景的KRAS-G12C突变型NSCLC新型治疗方法。
