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

Yael Kusne, Eugenio A. Carrera-Silva, Anthony S. Perry, Elisabeth J. Rushing, Edward K. Mandell, Justin D. Dietrich, Andrea E. Errasti, Daniel Gibbs, Michael E. Berens, Joseph C. Loftus, Christopher Hulme, Weiwei Yang, Zhimin Lu, Kenneth Aldape, Nader Sanai, Carla V. Rothlin, Sourav Ghosh

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Article numberra75
JournalScience Signaling
Volume7
Issue number338
DOIs
StatePublished - Aug 12 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kusne, Y., Carrera-Silva, E. A., Perry, A. S., Rushing, E. J., Mandell, E. K., Dietrich, J. D., Errasti, A. E., Gibbs, D., Berens, M. E., Loftus, J. C., Hulme, C., Yang, W., Lu, Z., Aldape, K., Sanai, N., Rothlin, C. V., & Ghosh, S. (2014). Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma. Science Signaling, 7(338), [ra75]. https://doi.org/10.1126/scisignal.2005196