%0 Journal Article %1 Zanca:2017:Genes-Dev:28724615 %A Zanca, C %A Villa, G R %A Benitez, J A %A Thorne, A H %A Koga, T %A D'Antonio, M %A Ikegami, S %A Ma, J %A Boyer, A D %A Banisadr, A %A Jameson, N M %A Parisian, A D %A Eliseeva, O V %A Barnabe, G F %A Liu, F %A Wu, S %A Yang, H %A Wykosky, J %A Frazer, K A %A Verkhusha, V V %A Isaguliants, M G %A Weiss, W A %A Gahman, T C %A Shiau, A K %A Chen, C C %A Mischel, P S %A Cavenee, W K %A Furnari, F B %D 2017 %J Genes Dev %K PAYWALL SHOULDREAD cancer-research glioblastoma %R 10.1101/gad.300079.117 %T Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity %U https://www.ncbi.nlm.nih.gov/pubmed/?term=Glioblastoma+cellular+cross-talk+converges+on+NF-%CE%BAB+to+attenuate+EGFR+inhibitor+sensitivity %X 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.

@article{Zanca:2017:Genes-Dev:28724615, 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.}, added-at = {2017-09-10T22:52:13.000+0200}, author = {Zanca, C and Villa, G R and Benitez, J A and Thorne, A H and Koga, T and D'Antonio, M and Ikegami, S and Ma, J and Boyer, A D and Banisadr, A and Jameson, N M and Parisian, A D and Eliseeva, O V and Barnabe, G F and Liu, F and Wu, S and Yang, H and Wykosky, J and Frazer, K A and Verkhusha, V V and Isaguliants, M G and Weiss, W A and Gahman, T C and Shiau, A K and Chen, C C and Mischel, P S and Cavenee, W K and Furnari, F B}, biburl = {https://www.bibsonomy.org/bibtex/2c47aa9579f606d20f8b28854c9bbb558/marcsaric}, description = {Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity. - PubMed - NCBI}, doi = {10.1101/gad.300079.117}, interhash = {61aabfe2ea1f6a938acf76859eb61dea}, intrahash = {c47aa9579f606d20f8b28854c9bbb558}, journal = {Genes Dev}, keywords = {PAYWALL SHOULDREAD cancer-research glioblastoma}, month = jul, pmid = {28724615}, timestamp = {2017-09-10T22:52:13.000+0200}, title = {Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity}, url = {https://www.ncbi.nlm.nih.gov/pubmed/?term=Glioblastoma+cellular+cross-talk+converges+on+NF-%CE%BAB+to+attenuate+EGFR+inhibitor+sensitivity}, year = 2017 }