Browsing by Author "Zanca, Ciro"

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    Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity
    (2017-06-15) Zanca, Ciro; Villa, Genaro R.; Benitez, Jorge A.; Thorne, Amy Haseley; Koga, Tomoyuki; D’Antonio, Matteo; Ikegami, Shiro; Ma, Jianhui; Boyer, Antonia D.; Banisadr, Afsheen; Jameson, Nathan M.; Parisian, Alison D.; Eliseeva, Olesja V.; Barnabe, Gabriela F.; Liu, Feng; Wu, Sihan; Yang, Huijun; Wykosky, Jill; Frazer, Kelly A.; Verkhusha, Vladislav V.; Isaguliants, Maria G.; Weiss, William A.; Gahman, Timothy C.; Shiau, Andrew K.; Chen, Clark C.; Mischel, Paul S.; Cavenee, Webster K.; Furnari, Frank B.; Research Department
    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.