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

Objective: More than half of human glioblastomas show EGFR gene amplification and mutation, but EGFR inhibitors have notbeen effective in treating EGFR-positive glioblastoma patients. The mechanism behind this type of primary resistance is not wellunderstood. The aim of this study was to investigate gefitinib resistance in glioblastoma, and explore ways to circumvent thissignificant 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 wasintroduced to measure the TNFα protein levels in cell culture supernatant of glioblastoma cells treated with gefitinib. Western blotwas used to detect the activity change of intracellular kinases in drug-treated glioblastoma cells. Two mouse xenograft tumormodels 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 signalingaxis, and that high TNFα levels in the glioblastoma microenvironment may further intensify primary resistance. A combination ofthe TNFα-specific small-molecule inhibitor C87 and gefitinib significantly enhanced the sensitivity of glioblastoma cells togefitinib in vitro and in vivo. Conclusions: Our findings provide a possible explanation for the primary resistance of glioblastoma to EGFR inhibitors andsuggest that dual blockade of TNFα and EGFR may be a viable therapeutic strategy for the treatment of patients withchemotherapy-refractory advanced glioblastoma. Cite this article as: Ma L, She C, Shi Q, Yin Q, Ji X, Wang Y, et al. TNFαinhibitor C87 sensitizes EGFRvIII transfected glioblastoma cells to gefitinib bya concurrent blockade of TNFα signaling. Cancer Biol Med. 2019; 16: 606-17.doi: 10.20892/j.issn.2095-3941.2019.0011