Abstract
Activation of aPKC by both EGFR and paracrine TNFα signaling promotes glioblastoma progression.
Major finding: Activation of aPKC by both EGFR and paracrine TNFα signaling promotes glioblastoma progression.
Concept: Myeloid cell–derived TNFα induces EGFR inhibitor resistance and aPKC-mediated NF-κB signaling.
Impact: Targeting aPKC may inhibit tumor cell–intrinsic and non–cell-autonomous signaling in glioblastoma.
Aberrant EGFR activation is frequently observed in glioblastoma, suggesting that inhibition of this receptor tyrosine kinase (RTK) may be therapeutically beneficial. However, EGFR kinase inhibitors have shown limited clinical efficacy due to activation of parallel and downstream oncogenic pathways that promote drug resistance, emphasizing the need to identify additional therapeutic strategies. Kusne, Carrera-Silva, and colleagues found that the expression of atypical protein kinase C (aPKC), a serine–threonine kinase implicated in neural development, was increased in glioblastoma samples compared with normal brain tissue and that high aPKC levels were correlated with shorter survival in patients with glioblastoma. Inhibition of aPKC reduced the growth of intracranial glioblastoma tumors in mice, including patient-derived EGFR inhibitor–resistant tumors, suggesting that aPKC promotes glioblastoma progression and that it may be a therapeutic target. aPKC was activated by EGFR as well as other RTKs in glioblastoma cells, and was also induced by TNFα produced by myeloid cells in the tumor microenvironment. Paracrine TNFα signaling stimulated NF-κB–dependent target gene expression in glioblastoma cells, enhanced glioblastoma cell proliferation and invasion, and promoted EGFR inhibitor resistance. The protumor activity of myeloid cell–derived TNFα was mediated by aPKC-dependent induction of NF-κB signaling; aPKC inhibition impaired NF-κB activation and suppressed tumor cell proliferation and invasion in coculture experiments, whereas constitutive aPKC activation was sufficient to trigger TNFα- and EGF-driven gene expression. Activation of aPKC by EGFR and TNFα resulted in the formation of distinct aPKC signaling complexes containing the scaffold proteins PAR6 or p62, respectively, resulting in specific induction of EGF and TNFα gene expression programs. These results identify a critical role for aPKC in glioblastoma progression via activation of parallel signaling pathways and suggest that targeting aPKC may facilitate inhibition of both tumor cell–autonomous and microenvironment-driven oncogenic signaling in glioblastoma.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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