2. Academic Validation
  3. Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

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

  • Genes Dev. 2017 Jun 15;31(12):1212-1227. doi: 10.1101/gad.300079.117.
Ciro Zanca 1,  Genaro R Villa 1 2 3,  Jorge A Benitez 1,  Amy Haseley Thorne 1,  Tomoyuki Koga 1,  Matteo D'Antonio 4,  Shiro Ikegami 1,  Jianhui Ma 1,  Antonia D Boyer 1,  Afsheen Banisadr 1,  Nathan M Jameson 1,  Alison D Parisian 1,  Olesja V Eliseeva 5,  Gabriela F Barnabe 1,  Feng Liu 1 6 7 8,  Sihan Wu 1,  Huijun Yang 1,  Jill Wykosky 1,  Kelly A Frazer 4 9 10,  Vladislav V Verkhusha 11,  Maria G Isaguliants 5 12 13,  William A Weiss 14 15 16,  Timothy C Gahman 1,  Andrew K Shiau 1,  Clark C Chen 4,  Paul S Mischel 1 4 17,  Webster K Cavenee 1 4 18,  Frank B Furnari 1 4 17
Affiliations

Affiliations

  • 1 Ludwig Institute for Cancer Research, La Jolla, California 92093, USA.
  • 2 Department of Molecular and Medical Pharmacology, School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
  • 3 Medical Scientist Training Program, School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
  • 4 Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.
  • 5 Gamaleya Research Center of Epidemiology and Microbiology, Moscow 123098, Russian Federation.
  • 6 National Research Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 7 State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 8 Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 9 Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
  • 10 Department of Pediatrics, Rady Children's Hospital, Division of Genome Information Sciences, University of California at San Diego, La Jolla, California 92093, USA.
  • 11 Department of Anatomy and Structural Biology, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
  • 12 Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm 17177, Sweden.
  • 13 Department of Research, Riga Stradins University, Riga LV-1007, Latvia.
  • 14 Department of Neurology, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94159, USA.
  • 15 Department of Pediatrics, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94159, USA.
  • 16 Department of Neurosurgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94159, USA.
  • 17 Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA.
  • 18 Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA.
PMID: 28724615 DOI: 10.1101/gad.300079.117
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.

Keywords

EGFR; IL-6; NF-κB; glioblastoma; survivin; tumor heterogeneity.

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