Primary resistance to EGFR inhibition in glioblastoma is mediated by a TNF-JNK-Axl-ERK signaling axis

Aberrant EGFR signaling is widespread in cancer, making the EGFR an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition has not been effective in treating this tumor. Here, we propose that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. We show that in glioma cells expressing either EGFR wild type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased TNF secretion that leads to activation of a TNF-JNK-Axl-ERK signaling axis. Inhibition of this adaptive axis at multiple nodes renders glioma cells with primary resistance sensitive to EGFR inhibition. Our findings provide a possible explanation for the multiple failures of anti-EGFR therapy in GBM and suggest a new approach to the treatment of EGFR expressing GBM using a combination of EGFR and TNF inhibition.