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Genes Dev. 2017 Jun 15;31(12):1212-1227. doi: 10.1101/gad.300079.117. Epub 2017 Jul 19.

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

Author information

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.

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

Comment in

PMID:
28724615
PMCID:
PMC5558924
DOI:
10.1101/gad.300079.117
[Indexed for MEDLINE]
Free PMC Article

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