Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells

Philip L. Lorenzi, William C. Reinhold, Martina Rudelius, Michele Gunsior, Uma Shankavaram, Kimberly J. Bussey, Uwe Scherf, Gabriel S. Eichler, Scott E. Martin, Koei Chin, Joe W. Gray, Elise C. Kohn, Ivan D. Horak, Daniel D. Von Hoff, Mark Raffeld, Paul K. Goldsmith, Natasha J. Caplen, John N. Weisntein

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

L-Asparaginase (L-ASP), a bacterial enzyme used since the 1970s to treat acute lymphoblastic leukemia, selectively starves cells that cannot synthesize sufficient asparagine for their own needs. Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase (ASNS) expression and DNA copy number with sensitivity to L-ASP in the leukemia and ovarian cancer cell subsets. To assess whether the ovarian relationship is causal, we used RNA interference to silence ASNS in three ovarian lines and observed 4- to 5-fold potentiation of sensitivity to L-ASP with two of the lines. For OVCAR-8, the line that expresses the least ASNS, the potentiation was > 500-fold. Significantly, that potentiation was > 700-fold in the multidrug-resistant derivative OVCAR-8/ADR, showing that the causal relationship between ASNS expression and L-ASP activity survives development of classical multidrug resistance. Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as other tumor types. Overall, this pharmaeogenomic/ pharmacoproteomic study suggests the use Of L-ASP for treatment of a subset of ovarian cancers (and perhaps other tumor types), with ASNS as a blomarker for patient selection.

Original languageEnglish (US)
Pages (from-to)2613-2623
Number of pages11
JournalMolecular cancer therapeutics
Volume5
Issue number11
DOIs
StatePublished - Nov 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells'. Together they form a unique fingerprint.

  • Cite this

    Lorenzi, P. L., Reinhold, W. C., Rudelius, M., Gunsior, M., Shankavaram, U., Bussey, K. J., Scherf, U., Eichler, G. S., Martin, S. E., Chin, K., Gray, J. W., Kohn, E. C., Horak, I. D., Von Hoff, D. D., Raffeld, M., Goldsmith, P. K., Caplen, N. J., & Weisntein, J. N. (2006). Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells. Molecular cancer therapeutics, 5(11), 2613-2623. https://doi.org/10.1158/1535-7163.MCT-06-0447