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<p>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.</p>

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Anlotinib enhances the efficacy of KRAS-G12C inhibitors through c-Myc/ORC2 axis inhibition in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月2日

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  • Hongyu Liu,
  • Chao Zhou,
  • Jun Lu,
  • Yuqing Liu,
  • Peichen Zou,
  • Liang Zhu,
  • Huimin Lei,
  • Baohui Han

摘要

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.