Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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CKD-516 potentiates the anti-cancer activity of docetaxel against epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer

  • Soo Jin, Kim (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Kyunghyeon, Lee (CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation) ;
  • Jaewoo, Park (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Miso, Park (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • U. Ji, Kim (CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation) ;
  • Se-mi, Kim (CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation) ;
  • Keun Ho, Ryu (CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation) ;
  • Keon Wook, Kang (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
  • Received : 2022.05.05
  • Accepted : 2022.07.12
  • Published : 2023.01.15
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Abstract

Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy; combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable; neither CKD-516 nor docetaxel affected the mean plasma concentration-time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858R/T790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

Keywords

Acknowledgement

This research was funded by the National Research Foundation of Korea (NRF) grant 2021R1A2C2093196.

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