Abstract
Aberrant EGFR signaling is widespread in various forms of cancer, but EGFR inhibition seems to be primarily effective only in a subset of lung cancers that harbor EGFR activating mutations and are oncogene addicted. Most cancers with aberrant EGFR signaling are not oncogene addicted and exhibit a primary resistance to EGFR inhibition. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition is not effective in treating this tumor. Primary resistance to EGFR inhibition could occur because the EGFR does not drive survival/proliferation of these cells or because adaptive signals prevent cell death. Our data suggest that EGFR expressing glioma cells exhibiting primary resistance are potentially oncogene addicted and that primary resistance results from a rapid adaptive response to EGFR inhibition that mediates cell survival. We show that in primary GBM neurospheres or cell lines expressing either EGFRwild type or the mutant EGFRvIII, erlotinib triggers a rapid adaptive response that is driven by tumor necrosis factor (TNF) and protects cells from a loss of EGFR signaling. Increased TNF secretion leads to JNK activation, which serves as a key regulator of this survival response. JNK activation results in increased levels of GAS6 and activation of Axl, leading to ERK activation. We propose that this TNFα-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in GBM. Inhibition of this adaptive response at multiple nodes renders glioma cells with primary resistance sensitive to EGFR inhibition. Moreover, combined treatment of erlotinib and thalidomide as a TNF inhibitor resulted a highly significant improved survival in intracranial mouse model using patient derived samples (n=8, p<0.01), whereas erlotinib or thalidomide alone were not effective. Our findings suggest a new approach to the treatment of GBM using a combination of EGFR and TNF inhibition.