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 journalArticlepeer-review

    32 Citations (Scopus)

    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
    Pages (from-to)1212-1227
    Number of pages16
    JournalGenes and Development
    Volume31
    Issue number12
    DOIs
    Publication statusPublished - 15 Jun 2017

    Keywords

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

    Field of Science

    • 1.6 Biological sciences

    Publication Type

    • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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