TNFα inhibitor C87 sensitizes EGFRvⅢ transfected glioblastoma cells to gefitinib by a concurrent blockade of TNFα signaling

【Author】

Li Ma;Chunhua She;Qian Shi;Qiang Yin;Xinxin Ji;Yongrong Wang;Yulong Fan;Xinyao Kong;Peng Li;Zengfeng Sun;Xiaohui Zhang;Zhen Zhang;Jian Wang;Tong Wang;Yuanfu Xu;Wenliang Li;Department of Neuro-Oncology and Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy,Tianjin, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer;State Key Laboratory of Experimental Hematology, CAMS Key Laboratory for Prevention and Control of Hematological Disease Treatment Related Infection, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College;Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy,Tianjin, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer;

【Institution】

Department of Neuro-Oncology and Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy,Tianjin, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer;State Key Laboratory of Experimental Hematology, CAMS Key Laboratory for Prevention and Control of Hematological Disease Treatment Related Infection, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College;Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy,Tianjin, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer;

【Abstract】

Objective: More than half of human glioblastomas show EGFR gene amplification and mutation, but EGFR inhibitors have not been effective in treating EGFR-positive glioblastoma patients.The mechanism behind this type of primary resistance is not well understood.The aim of this study was to investigate gefitinib resistance in glioblastoma, and explore ways to circumvent this significant clinical problem.Methods: MTT method was used to test the cell viability after EGFR-positive glioblastoma cells were treated with indicated drugs;real-time quantitative PCR method was included to detect the TNFα mRNA levels in glioma tissues and cell lines.ELISA was introduced to measure the TNFα protein levels in cell culture supernatant of glioblastoma cells treated with gefitinib.Western blot was used to detect the activity change of intracellular kinases in drug-treated glioblastoma cells.Two mouse xenograft tumor models were carried out to evaluate the in vivo effects of a combination of EGFR and TNFα inhibitors.Results: We found that glioblastoma resistance to gefitinib may be mediated by an adaptive pro-survival TNFα-JNK-Axl signaling axis, and that high TNFα levels in the glioblastoma microenvironment may further intensify primary resistance.A combination of the TNFα-specific small-molecule inhibitor C87 and gefitinib significantly enhanced the sensitivity of glioblastoma cells to gefitinib in vitro and in vivo.Conclusions: Our findings provide a possible explanation for the primary resistance of glioblastoma to EGFR inhibitors and suggest that dual blockade of TNFα and EGFR may be a viable therapeutic strategy for the treatment of patients with chemotherapy-refractory advanced glioblastoma.

【Keywords】

Glioblastoma;;EGFR;;TNFα;;inhibitor;;drug resistance

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Total: 24 articles

  • [1] Yang Chen;Youyou Wang;Lujun Zhao;Ping Wang;Jifeng Sun;Rudi Bao;Chenghai Li;Ningbo Liu;Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin;Tianjin's Clinical Research Center for Cancer;Jiangsu Hansoh Pharmaceutical Co., Ltd;, EGFR tyrosine kinase inhibitor HS-10182 increases radiation sensitivity in non-small cell lung cancers with EGFR T790M mutation, Cancer Biology & Medicine,
  • [2] Yuchen Bai;Xiaoxia Chen;Likun Hou;Jun Qian;Tao Jiang;Caicun Zhou;Maciej Ciebiada;Department of General and Oncological Pulmonology, University Clinical Hospital Norbert Barlicki, Medical University of Lodz;Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine;Department of Medical Oncology, Shanghai Jiao Tong University School of Medicine;Department of Pathology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine;Department of Medical Oncology, Suzhou Cancer Center, the Affiliated Suzhou Hospital of Nanjing Medical University;, PD-L1 expression and its effect on clinical outcomes of EGFRmutant NSCLC patients treated with EGFR-TKIs, Cancer Biology & Medicine,
  • [3] Roel G.W. Verhaak;;Katherine A. Hoadley;;Elizabeth Purdom;;Victoria Wang;;Yuan Qi;;Matthew D. Wilkerson;;C. Ryan Miller;;Li Ding;;Todd Golub;;Jill P. Mesirov;;Gabriele Alexe;;Michael Lawrence;;Michael O'Kelly;;Pablo Tamayo;;Barbara A. Weir;;Stacey Gabriel;;Wendy Winckler;;Supriya Gupta;;Lakshmi Jakkula;;Heidi S. Feiler;;J. Graeme Hodgson;;C. David James;;Jann N. Sarkaria;;Cameron Brennan;;Ari Kahn;;Paul T. Spellman;;Richard K. Wilson;;Terence P. Speed;;Joe W. Gray;;Matthew Meyerson;;Gad Getz;;Charles M. Perou;;D. Neil Hayes, Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA , IDH1 , EGFR , and NF1, Cancer Cell,
  • [4] Shaan M. Raza;;Frederick F. Lang;;Bharat B. Aggarwal;;Gregory N. Fuller;;David M. Wildrick;;Raymond Sawaya, Necrosis and Glioblastoma: A Friend or a Foe? A Review and a Hypothesis, Neurosurgery,

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