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

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.

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

“…A similar response was observed in our previous study (26). The presence of JQ1 not only suppressed basal survivin expression, consistent with others' results (47,48), but also the strong induction of survivin by PDT (Fig. 10A).…”

“…inhibited for survivin and Bcl-xL, and reversed for p21. JQ1 may have down-regulated survivin directly by blocking its transcription (47,48). However, an indirect effect due to iNOS down-regulation was also possible, since NO is known to signal for survivin induction (49,50).…”

The power of the few

“…Taken together, the findings reported by Zanca et al (2017) provide a conceptual framework in which the collective behavior of the tumor is defined by the adaptive mechanisms and circuits initiated and orchestrated by a small population of tumor cells. With a greater understanding of these interconnections, future therapies might emerge that target these bionetworks at multiple nodes of vulnerability.…”

“…In keeping with the power of the few, Furnari and colleagues (Zanca et al 2017) now report that a small population of cancer cells in high-grade brain tumors (glioblastoma) can orchestrate the complex behavior of the entire tumor. Glioblastomas are deadly malignancies characterized by significant cellular and molecular heterogeneity.…”

“…In this issue of Genes & Development, Zanca et al (2017) demonstrate that EGFRvIII mutant glioblastoma cells control the survival of wild-type (nonmutant) EGFR-expressing glioblastoma cells as well as provide a unique escape mechanism for evading therapeutic RTK inhibition. These studies identified interleukin-6 (IL-6), secreted by EGFRvIII mutant glioblastoma cells, as an anti-apoptotic effector responsible for attenuating glioblastoma cell sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy.…”