Molecular network pathways and functional analysis of tumor signatures associated with development of resistance to viral gene therapy

T. J. Song, D. Haddad, P. Adusumilli, T. Kim, B. Stiles, M. Hezel, N. D. Socci, M. Gönen, Y. Fong

    Research output: Contribution to journalArticlepeer-review

    3 Citations (Scopus)

    Abstract

    Replication-competent attenuated herpes simplex viruses have proven effective in killing many cancer cell lines. However, determinants of resistance to oncolytic therapy are mostly unknown. We developed viral therapy-resistant cells and examined changes in gene-expression pattern compared with therapy-sensitive parental cells. Colon cancer cell line HT29 and hepatoma cell line PLC5 were exposed to increasing concentrations of virus G207. Therapy-resistant cells were isolated and grown in vitro. Tumorigenicity was confirmed by ability of cell lines to form tumors in mice. Human Genome U133A complementary DNA microarray chips were used to determine gene-expression patterns, which were analyzed in the context of molecular network interactions, pathways and gene ontology. In parental cell lines, 90-100% of cells were killed by day 7 at 1.0 multiplicity of infection. In resistant cell lines, cytotoxicity assay confirmed 200-to 400-fold resistance. Microarray analysis confirmed changes in gene expressions associated with resistance: cell surface proteins affecting viral attachment and entry, cellular proteins affecting nucleotide pools and proteins altering apoptotic pathways. These changes would decrease viral infection and replication. Our study identifies gene-expression signatures associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for trial with this novel treatment.

    Original languageEnglish
    Pages (from-to)38-48
    Number of pages11
    JournalCancer Gene Therapy
    Volume19
    Issue number1
    DOIs
    Publication statusPublished - 2012 Jan

    Keywords

    • G207
    • herpes simplex virus
    • molecular networks
    • oncolytic viral therapy
    • signaling pathways

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology
    • Cancer Research

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