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

Authors: Song, T. J.; Haddad, D.; Adusumilli, P.; Kim, T.; Stiles, B.; Hezel, M.; Socci, N. D.; Gonen, M.; Fong, Y.
Article Title: Molecular network pathways and functional analysis of tumor signatures associated with development of resistance to viral gene therapy
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. © 2012 Nature America, Inc. All rights reserved.
Keywords: controlled study; human cell; nonhuman; mouse; cell death; mus; apoptosis; gene expression; animal experiment; animal model; cancer cell culture; cytotoxicity; in vitro study; microarray analysis; carcinogenicity; cell isolation; simplexvirus; dna microarray; virus replication; herpes simplex virus; cell strain ht29; complementary dna; virus attachment; cell surface protein; signaling pathways; g 207; virus entry; herpes virus infection; viral gene therapy; oncolytic viral therapy; g207; molecular networks; hepatoma cell
Journal Title: Cancer Gene Therapy
Volume: 19
Issue: 1
ISSN: 0929-1903
Publisher: Nature Publishing Group  
Date Published: 2012-01-01
Start Page: 38
End Page: 48
Language: English
DOI: 10.1038/cgt.2011.64
PROVIDER: scopus
PUBMED: 22015641
Notes: --- - "Export Date: 3 January 2012" - "CODEN: CGTHE" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Mithat Gonen
    934 Gonen
  2. Yuman Fong
    774 Fong
  3. Dana Haddad
    21 Haddad
  4. Taejin Song
    7 Song
  5. Nicholas D Socci
    240 Socci
  6. Teresa Sora Kim
    23 Kim
  7. Brendon Stiles
    25 Stiles
  8. Michael Hezel
    19 Hezel