TNF Inhibitor Pomalidomide Sensitizes Glioblastoma Cells to EGFR Inhibition.

ABSTRACT

OBJECTIVE: Epidermal growth factor receptor (EGFR) is one of the important targets in cancer treatment. However, EGFR inhibitors are reported to be ineffective in treating glioblastoma (GBM). In this study, we evaluated the potential mechanism of GBM resistance to EGFR inhibition. METHODS: EGFR, p38, extracellular signal-related kinase (ERK), and c-Jun N-terminal kinase (JNK) expression levels were detected by western blotting. Cell viability was evaluated by the MTT assay. Tumor necrosis factor (TNF) mRNA expression was assessed by qRT-PCR. TNF-α expression was detected by ELISA. The combined effect of EGFR inhibitor (afatinib) and TNF inhibitor (pomalidomide) was evaluated in xenograft athymic mouse model of GBM. RESULTS: Upon blocking TNF, GBM sensitivity to EGFR inhibitors was observed to recover. The combination of afatinib and pomalidomide was found to effectively inhibit cell growth of EG-FR-expressing GBM. In addition, the p38/JNK/ERK pathway was activated following EGFR inhibition. CONCLUSIONS: We demonstrated that GBM resistance to EGFR inhibition was mediated by the activation of TNF. The combination of EGFR inhibitor and TNF inhibitor may have potential clinical implication in treating patients with EGFR-positive GBM.