Functional Genomics Reveals Diverse Cellular Processes That Modulate Tumor Cell Response to Oxaliplatin

  • Harradine K
  • Kassner M
  • Chow D
 et al. 
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Abstract

Oxaliplatin is widely used to treat colorectal cancer, as both adjuvant
therapy for resected disease and palliative treatment of metastatic
disease. However, a significant number of patients experience serious
side effects, including prolonged neurotoxicity, from oxaliplatin
treatment creating an urgent need for biomarkers of oxaliplatin response
or resistance to direct therapy to those most likely to benefit. As a
first step to improve selection of patients for oxaliplatin-based
chemotherapy, we have conducted an in vitro cell-based small interfering
RNA (siRNA) screen of 500 genes aimed at identifying genes whose loss of
expression alters tumor cell response to oxaliplatin. The siRNA screen
identified twenty-seven genes, which when silenced, significantly
altered colon tumor cell line sensitivity to oxaliplatin. Silencing of a
group of putative resistance genes increased the extent of
oxaliplatin-mediated DNA damage and inhibited cell-cycle progression in
oxaliplatin-treated cells. The activity of several signaling nodes,
including AKT1 and MEK1, was also altered. We used cDNA transfection to
overexpress two genes (LTBR and TMEM30A) that were identified in the
siRNA screen as mediators of oxaliplatin sensitivity. In both instances,
overexpression conferred resistance to oxaliplatin. In summary, this
study identified numerous putative predictive biomarkers of response to
oxaliplatin that should be studied further in patient specimens for
potential clinical application. Diverse gene networks seem to influence
tumor survival in response to DNA damage by oxaliplatin. Finally, those
genes whose loss of expression (or function) is related to oxaliplatin
sensitivity may be promising therapeutic targets to increase patient
response to oxaliplatin. Mol Cancer Res; 9(2); 173-82. (C) 2010 AACR.

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Authors

  • Kelly A Harradine

  • Michelle Kassner

  • Donald Chow

  • Meraj Aziz

  • Daniel D Von Hoff

  • Joffre B Baker

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