26 research outputs found
American Catholics: Persisting and Changing: Morning Session. Persistence and Change in the Catholic Landscape
American Catholics: Persisting and Changing: Afternoon Session. Millennials: Hispanic and Non-Hispanic Catholics, A Glimpse of the Decade Ahead
Directions in Social Science - Donald P. Ray (ed.): Trends in Social Science. (New York: Philosophical Library, 1961. Pp. 169. $4.75.)
Differential Patterns of Community Power Structure: An Explanation Based on Interdependence
Putting Politics First: The Impact of Politics on American Religious and Secular Orientations
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Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity
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