Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Ciro Zanca, Genaro R. Villa, Jorge A. Benitez, Amy Haseley Thorne, Tomoyuki Koga, Matteo D’Antonio, Shiro Ikegami, Jianhui Ma, Antonia D. Boyer, Afsheen Banisadr, Nathan M. Jameson, Alison D. Parisian, Olesja V. Eliseeva, Gabriela F. Barnabe, Feng Liu, Sihan Wu, Huijun Yang, Jill Wykosky, Kelly A. Frazer, Vladislav V. VerkhushaMaria G. Isaguliants, William A. Weiss, Timothy C. Gahman, Andrew K. Shiau, Clark C. Chen, Paul S. Mischel, Webster K. Cavenee, Frank B. Furnari

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.

Original languageEnglish (US)
Pages (from-to)1212-1227
Number of pages16
JournalGenes and Development
Volume31
Issue number12
DOIs
StatePublished - Jun 15 2017

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Keywords

  • EGFR
  • Glioblastoma
  • IL-6
  • NF-κB
  • Survivin
  • Tumor heterogeneity

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Zanca, C., Villa, G. R., Benitez, J. A., Thorne, A. H., Koga, T., D’Antonio, M., Ikegami, S., Ma, J., Boyer, A. D., Banisadr, A., Jameson, N. M., Parisian, A. D., Eliseeva, O. V., Barnabe, G. F., Liu, F., Wu, S., Yang, H., Wykosky, J., Frazer, K. A., ... Furnari, F. B. (2017). Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity. Genes and Development, 31(12), 1212-1227. https://doi.org/10.1101/gad.300079.117