A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma

Gao Guo, Ke Gong, Sonia Ali, Neha Ali, Shahzad Shallwani, Kimmo J. Hatanpaa, Edward Pan, Bruce Mickey, Sandeep Burma, David H. Wang, Santosh Kesari, Jann N Sarkaria, Dawen Zhao, Amyn A. Habib

Research output: Contribution to journalArticle

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Abstract

Aberrant epidermal growth factor receptor (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 tumor necrosis factor (TNF) secretion, which leads to activation in turn of c-Jun N-terminal kinase (JNK), the Axl receptor tyrosine kinase and extracellular signal-regulated kinases (ERK). Inhibition of this adaptive axis at multiple nodes rendered glioma cells with primary resistance sensitive to EGFR inhibition. Our findings provide a possible explanation for the 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.

Original languageEnglish (US)
Pages (from-to)1074-1084
Number of pages11
JournalNature Neuroscience
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2017

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JNK Mitogen-Activated Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Glioblastoma
Epidermal Growth Factor Receptor
Tumor Necrosis Factor-alpha
Glioma
erbB-1 Genes
Gene Amplification
Neoplasms
Cell Survival

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Guo, G., Gong, K., Ali, S., Ali, N., Shallwani, S., Hatanpaa, K. J., ... Habib, A. A. (2017). A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. Nature Neuroscience, 20(8), 1074-1084. https://doi.org/10.1038/nn.4584

A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. / Guo, Gao; Gong, Ke; Ali, Sonia; Ali, Neha; Shallwani, Shahzad; Hatanpaa, Kimmo J.; Pan, Edward; Mickey, Bruce; Burma, Sandeep; Wang, David H.; Kesari, Santosh; Sarkaria, Jann N; Zhao, Dawen; Habib, Amyn A.

In: Nature Neuroscience, Vol. 20, No. 8, 01.08.2017, p. 1074-1084.

Research output: Contribution to journalArticle

Guo, G, Gong, K, Ali, S, Ali, N, Shallwani, S, Hatanpaa, KJ, Pan, E, Mickey, B, Burma, S, Wang, DH, Kesari, S, Sarkaria, JN, Zhao, D & Habib, AA 2017, 'A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma', Nature Neuroscience, vol. 20, no. 8, pp. 1074-1084. https://doi.org/10.1038/nn.4584
Guo, Gao ; Gong, Ke ; Ali, Sonia ; Ali, Neha ; Shallwani, Shahzad ; Hatanpaa, Kimmo J. ; Pan, Edward ; Mickey, Bruce ; Burma, Sandeep ; Wang, David H. ; Kesari, Santosh ; Sarkaria, Jann N ; Zhao, Dawen ; Habib, Amyn A. / A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. In: Nature Neuroscience. 2017 ; Vol. 20, No. 8. pp. 1074-1084.
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