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Sci Signal. 2014 Aug 12;7(338):ra75. doi: 10.1126/scisignal.2005196.

Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma.

Author information

1
Neuroscience Graduate Program, Arizona State University, Phoenix, AZ 85287, USA.
2
Barrow Brain Tumor Research Center, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Pathology, Banner MD Anderson Cancer Center, Gilbert, AZ 85234, USA.
5
Armed Forces Institute of Pathology, Washington, DC 20306-0003, USA.
6
Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA.
7
Bio5OV, The University of Arizona, Oro Valley, AZ 85737, USA.
8
Department of Neurosciences, University of California, San Diego, San Diego, CA 92093, USA.
9
Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
10
Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
11
MD Anderson Cancer Center, Houston, TX 77030, USA.
#
Contributed equally

Abstract

Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-α (TNFα) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFα-dependent activation of the transcription factor nuclear factor κB (NF-κB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.

PMID:
25118327
PMCID:
PMC4486020
DOI:
10.1126/scisignal.2005196
[Indexed for MEDLINE]
Free PMC Article

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