Journal
ANNALS OF TRANSLATIONAL MEDICINE
Volume 7, Issue 22, Pages -Publisher
AME PUBL CO
DOI: 10.21037/atm.2019.10.80
Keywords
Head and neck; dihydroartemisinin (DHA); osimertinib; repurposing drug; drug combination
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Funding
- La Caixa Foundation
- Instituto de Salud Carlos III [PI14/01678]
- Marie Sklodowska-Curie Innovative Training Networks European Grant [765492]
- Spanish Association Against Cancer (AECC) [PROYE18012ROSE]
- Major National Science and Technology Program of China [2017ZX09101002-002-006]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)
- Key RAMP
- D Program of Jiangsu Province [BE2018755]
- National Natural Science Foundation of China [81573665]
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Background: Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis with limited progression-free survival and overall survival, even when treated with different combinations of chemotherapy, targeted therapies and immunotherapy. We explored in vitro and in vivo the effect of the epidermal growth factor receptor (EGFR) inhibitor, osimertinib, alone and in combination with dihydroartemisinin (DHA) in HNSCC. Methods: The combination of osimertinib with DHA was tested in the FaDu and CAL27 HNSCC cell lines. Tumor cell proliferation assays were conducted in cultured cells and mouse xenografts. Western blotting analysis of related signal pathways was performed to investigate the molecular mechanisms of the inhibitory effect of DHA and the combination. Other compounds, which inhibit signal transducer and activator of transcription 3 (STAT3), Src-family kinases (SFKs), sphingosine kinase 1 (SPHK1), or the receptor tyrosine kinase (RTK) AXL were also combined with osimertinib in vitro. Results: Osimertinib exerted synergistic cytotoxicity toward FaDu and CAL27 HNSCC cells when combined with DHA. DHA reversed the osimertinib-induced STAT3 and Src phosphorylation. The double combination inhibited AXL expression. The anticancer potential of osimertinib plus DHA combination was validated in vivo on FaDu and CAL27 xenografts in mice without notable side effects. Conclusions: The results illustrate that the combinatory therapy of osimertinib and DHA, as a repurposing anticancer drug, could be a novel therapeutic strategy for recurrent and/or metastatic HNSCC patients. The findings strongly indicate that a clinical trial is warranted to confirm the benefit of the combination.
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