DRES-17. ACTIVATION OF FGF SIGNALING PATHWAY CONFERS RESISTANCE TO EGFR INHIBITION IN GBM. (5th November 2018)

• Record Type: Journal Article
• Authors: Guo, Gao; Gong, Ke; Sarkaria, Jann; Habib, Amyn
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi79
• Page End: vi79
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.324
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Amplification and mutation of the EGFR gene is a signature lesion in GBM and occurs in 40–50% of GBM patients. However, EGFR inhibition has been ineffective in the treatment of GBM. Resistance to EGFR inhibition may be primary or secondary after an initial period of susceptibility suggesting that adaptive mechanisms may mediate resistance to EGFR inhibition The adaptive response to EGFR inhibition is multifaceted. We have recently reported that TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in GBM cells 1 . We now report that the FGF (fibroblast growth factor) signaling pathway is activated by EGFR inhibition in GBM. A number of studies have identified the FGF signaling pathways as important pro-oncogenic signals in cancer and in mediating resistance to treatment. Our data indicate that the FGFR pathway is an additional candidate for mediating the adaptive response to EGFR inhibition. We find that in glioma cells expressing either EGFRwt or the mutant EGFRvIII, EGFR inhibition with erlotinib induces FGF1 and FGF3 expression at both mRNA and protein levels. Additionally, erlotinib exposure leads to phosphorylation of FGFR1 in multiple GBM cell lines. Knockdown of FGFR1 sensitized GBM cells to EGFR inhibition. Moreover, combined treatment of erlotinib and FGFR selective inhibitors such as Debio-1347 or AZD4547 significantly increased cell death versus in either drug alone in multiple GBM cell lines. Our findings suggest that combined EGFR and FGF inhibition could be an effective alternative approach to treating GBM. 1. Guo G, et al. A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. Nat Neurosci. 2017;20(8):1074–1084.