Imane Chaib1, Xueting Cai2,3, David Llige1, Mariacarmela Santarpia4, Eloisa Jantus-Lewintre5,6,7, Martyna Filipska1, Carlos Pedraz1, Jean Cui8, Jie Yang2, Jing Miao2, Rongwei Sun2, Jillian Wilhelmina Paulina Bracht9, Masaoki Ito9, Jordi Codony-Servat9, Niki Karachaliou10, Andrés Aguilar10, Rafael Rosell1,9,10,11, Peng Cao2,3,12. 1. Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain. 2. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China. 3. College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. 4. Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy. 5. Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain. 6. CIBERONC, Valencia, Spain. 7. Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain. 8. TP Therapeutics, Inc., San Diego, CA, USA. 9. Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, Spain. 10. Instituto Oncológico Dr. Rosell (IOR), University Hospital Sagrat Cor, Barcelona, Spain. 11. Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain. 12. 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.
Abstract
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. 2019 Annals of Translational Medicine. All rights reserved.
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. 2019 Annals of Translational Medicine. All rights reserved.
Entities:
Keywords:
Head and neck; dihydroartemisinin (DHA); drug combination; osimertinib; repurposing drug
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