2. Academic Validation
  3. Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis

Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis

  • Pharmacol Res. 2023 Jan 18;188:106668. doi: 10.1016/j.phrs.2023.106668.
Tianyao Lei 1,  Tianwei Xu 2,  Niu Zhang 3,  Xiaoteng Zou 4,  Ziyue Kong 5,  Chenchen Wei 6,  Zhaoxia Wang 7
Affiliations

Affiliations

  • 1 Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, PR China. Electronic address: ltynjmu@163.com.
  • 2 Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, PR China. Electronic address: xutianwei1993_njmu@foxmail.com.
  • 3 Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, PR China. Electronic address: 1207336873@qq.com.
  • 4 Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, PR China. Electronic address: fyodor@stu.njmu.edu.cn.
  • 5 Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, PR China. Electronic address: 425967683@qq.com.
  • 6 Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, PR China. Electronic address: weichenchen1990@126.com.
  • 7 Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, PR China. Electronic address: wangzhaoxia@njmu.edu.cn.
PMID: 36681369 DOI: 10.1016/j.phrs.2023.106668
Abstract

Favorable clinical evidence suggests that the next trend in new treatments for advanced non-small cell lung Cancer (NSCLC) will be combination therapies. However, inevitable epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance greatly limits the clinical efficacy of patients carrying EGFR-activating mutants. In this study, we found a patient with clinical osimertinib resistance who regained a positive response after osimertinib plus anlotinib treatment. Two osimertinib-resistant cell lines were constructed, and Axl conferred resistance to osimertinib in NSCLC cell lines. The combined effects of anlotinib and osimertinib restored sensitivity to osimertinib in two osimertinib-resistant NSCLC cell lines and in xenografts. Moreover, anlotinib inhibits the phosphorylation of Axl in both resistant cell lines. Mechanistically, we confirmed that MYC binds to the promoter of Axl to promote its transcription in NSCLC cells, and we demonstrated that anlotinib combined with osimertinib treatment enhances the anti-tumor effect by inactivating the c-MET/MYC/Axl axis to reverse osimertinib resistance in NSCLC. In conclusion, our results provide strong support that this combination therapy may be effective in enhancing the efficacy of treatments in patients with advanced NSCLC.

Keywords

AXL; Anlotinib; Anlotinib(PubChem CID: 25017411); EGFR-TKIs resistance; NSCLC; Osimertinib; Osimertinib(PubChem CID: 71496458); SGI-7079(PubChem CID: 46870258); Savolitinib(PubChem CID: 68289010).

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