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

  • Cell Death Dis. 2025 May 2;16(1):356. doi: 10.1038/s41419-025-07687-w.
Hongyu Liu  #  1 ,  Chao Zhou  #  1 ,  Jun Lu  1 ,  Yuqing Liu  2 ,  Peichen Zou  2 ,  Liang Zhu  2 ,  Huimin Lei  3 ,  Baohui Han  4
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 4. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 40316534 DOI: 10.1038/s41419-025-07687-w
Abstract

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.

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