2. Academic Validation
  3. Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer

Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer

  • Pharmacol Res. 2021 Aug;170:105701. doi: 10.1016/j.phrs.2021.105701.
Xueting Cai 1,  Jing Miao 2,  Rongwei Sun 2,  Sainan Wang 2,  Miguel Angel Molina-Vila 3,  Imane Chaib 4,  Rafael Rosell 5,  Peng Cao 6
Affiliations

Affiliations

  • 1 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
  • 2 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
  • 3 Laboratory of Molecular Biology, Pangaea Oncology, Quirón-Dexeus University Institute, Barcelona 08028, Spain.
  • 4 Laboratory of Molecular Biology, Institut d´Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona 08916, Spain.
  • 5 Laboratory of Molecular Biology, Institut d´Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona 08916, Spain. Electronic address: rrosell@iconcologia.net.
  • 6 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; College of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing 210023, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: cao_peng@njucm.edu.cn.
PMID: 34087353 DOI: 10.1016/j.phrs.2021.105701
Abstract

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is commonly used to treat EGFR-mutant non-small-cell lung Cancer (NSCLC). However, acquired resistance to mutant EGFR (T790M) can evolve following osimertinib treatment. High Reactive Oxygen Species (ROS) levels in lung Cancer cells can influence heme levels and have an impact on osimertinib resistance. Here, we found that heme levels were increased in osimertinib resistant EGFR-mutant NSCLC cell lines and plasma heme levels were also elevated in osimertinib-treated EGFR-mutant NSCLC patients. The antimalarial drug dihydroartemisinin (DHA), which has Anticancer effects and requires heme, was tested to determine its potential to revert osimertinib resistance. DHA downregulated the expression of heme oxygenase 1 and inhibited cell proliferation in osimertinib-resistant EGFR-mutant NSCLC cells (PC9-GR4-AZD1), which was further enhanced by addition of 5-aminolevulinic acid, protoporphyrin IX and hemin. DHA was synergistic with osimertinib in inhibiting cell proliferation and colony formation of all osimertinib-resistant cell lines tested. Combination treatment with osimertinib and DHA also increased the levels of ROS, downregulated the phosphorylation or protein levels of several RTKs that often are overexpressed in osimertinib-resistant EGFR-mutant NSCLC cells, and inhibited tumor growth without toxicity in a PC9-GR4-AZD1 xenograft mouse model. The results suggest that DHA is able to reverse the resistance to osimertinib in EGFR-mutant NSCLC by elevating ROS level and impair heme metabolism.

Keywords

Acquired resistance; Dihydroartemisinin; Heme; Non-small cell lung cancer; Osimertinib.

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