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- W2736974222 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." @default.
- W2736974222 created "2017-07-31" @default.
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- W2736974222 date "2017-06-15" @default.
- W2736974222 modified "2023-10-16" @default.
- W2736974222 title "Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity" @default.
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- W2736974222 doi "https://doi.org/10.1101/gad.300079.117" @default.
- W2736974222 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5558924" @default.
- W2736974222 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28724615" @default.
- W2736974222 hasPublicationYear "2017" @default.
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