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

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dc.contributor.authorZanca, Ciro
dc.contributor.authorVilla, Genaro R.
dc.contributor.authorBenitez, Jorge A.
dc.contributor.authorThorne, Amy Haseley
dc.contributor.authorKoga, Tomoyuki
dc.contributor.authorD’Antonio, Matteo
dc.contributor.authorIkegami, Shiro
dc.contributor.authorMa, Jianhui
dc.contributor.authorBoyer, Antonia D.
dc.contributor.authorBanisadr, Afsheen
dc.contributor.authorJameson, Nathan M.
dc.contributor.authorParisian, Alison D.
dc.contributor.authorEliseeva, Olesja V.
dc.contributor.authorBarnabe, Gabriela F.
dc.contributor.authorLiu, Feng
dc.contributor.authorWu, Sihan
dc.contributor.authorYang, Huijun
dc.contributor.authorWykosky, Jill
dc.contributor.authorFrazer, Kelly A.
dc.contributor.authorVerkhusha, Vladislav V.
dc.contributor.authorIsaguliants, Maria G.
dc.contributor.authorWeiss, William A.
dc.contributor.authorGahman, Timothy C.
dc.contributor.authorShiau, Andrew K.
dc.contributor.authorChen, Clark C.
dc.contributor.authorMischel, Paul S.
dc.contributor.authorCavenee, Webster K.
dc.contributor.authorFurnari, Frank B.
dc.contributor.institutionResearch Department
dc.date.accessioned2021-06-15T09:40:01Z
dc.date.available2021-06-15T09:40:01Z
dc.date.issued2017-06-15
dc.descriptionFunding Information: We thank Dr. David James, Dr. Frederick Lang, Dr. Cameron Brennan, and Dr. Harley Kornblum for GBM-PDX neurospheres. We thank Dr. Karen Arden for continuous support and critical evaluation of the results. We thank Dr. Robert Davis, Dr. German Gomez, Dr. Tiffany Taylor, Dr. Rachel Reed, Dr. Melissa Mcalonis, and Dr. Sora Lee for technical support. In memory of Rosa Lupo. This work was supported by the Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society (F.B.F. and P.S.M.), R01-NS080939 (F.B.F.), the James S. McDonnell Foundation (F.B.F.), the National Cancer Institute (2T32CA009523-29A1) (A.H.T), and 1RO1NS097649-01 (C.C.C.). C.Z. was partially supported by an American-Italian Cancer Foundation post-doctoral research fellowship. F.L. received a Gao Feng Gao Yuan Scholarship Award. T.C.G., A.K.S., P.S.M., W.K.C., and F.B.F. receive salary and additional support from the Ludwig Institute for Cancer Research. Publisher Copyright: © 2017 Zanca et al.
dc.description.abstractIn 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.en
dc.description.statusPeer reviewed
dc.format.extent16
dc.format.extent10388410
dc.identifier.citationZanca, C, Villa, G R, Benitez, J A, Thorne, A H, Koga, T, D’Antonio, M, Ikegami, S, Ma, J, Boyer, A D, Banisadr, A, Jameson, N M, Parisian, A D, Eliseeva, O V, Barnabe, G F, Liu, F, Wu, S, Yang, H, Wykosky, J, Frazer, K A, Verkhusha, V V, Isaguliants, M G, Weiss, W A, Gahman, T C, Shiau, A K, Chen, C C, Mischel, P S, Cavenee, W K & Furnari, F B 2017, 'Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity', Genes and Development, vol. 31, no. 12, pp. 1212-1227. https://doi.org/10.1101/gad.300079.117
dc.identifier.doi10.1101/gad.300079.117
dc.identifier.issn0890-9369
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/5031
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85027005612&partnerID=8YFLogxK
dc.language.isoeng
dc.relation.ispartofGenes and Development
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectEGFR
dc.subjectGlioblastoma
dc.subjectIL-6
dc.subjectNF-κB
dc.subjectSurvivin
dc.subjectTumor heterogeneity
dc.subject1.6 Biological sciences
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectGenetics
dc.subjectDevelopmental Biology
dc.titleGlioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivityen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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