Originally published as JCO Early Release 10.1200/JCO.2005.02.9405 on December 19 2005

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Tumor Necrosis Factor-–Induced Protein 3 As a Putative Regulator of Nuclear Factor-B–Mediated Resistance to O⁶-Alkylating Agents in Human Glioblastomas

From the Division of Oncology, Center for Clinical Sciences Research, Institute for Computational and Mathematical Engineering, Departments of Neurosurgery, Pathology, and Neurology, Stanford University School of Medicine, Stanford, CA; Ina Levine Brain Tumor Center, Neuro-Oncology Research and Neurosurgery Research, Barrow Neurological Institute of St. Joseph's Hospital and Medical Center, Phoenix, AZ; and the Department of General Neurosurgery, Neurocenter, University of Freiburg, Freiburg, Germany

Address reprint requests to Markus Bredel, MD, PhD, Division of Oncology, Stanford University School of Medicine, 269 Campus Dr, CCSR-1105, Stanford, CA 94305-5151; e-mail: mbredel{at}stanford.edu

PURPOSE: Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas.

METHODS: We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O⁶-alkylating agents in glioblastoma cells.

RESULTS: We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-B (NF-B), which included the persistent alterations of various NF-B pathway elements. Tumor necrosis factor-–induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-B activation in response to DNA damage caused by O⁶-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-B activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022).

CONCLUSION: Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-B en route to O⁶-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.

Supported by National Institutes of Health Grant No. CA 92474 (B.I.S.), Emmy-Noether-Program of the German Research Society (M.B.), and the Barrow Neurological Foundation (A.C.S.).

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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