Spotlight on Molecular Profiling

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

^{1 1}Genomics and Bioinformatics Group, Laboratory of Molecular Pharmacology, ²Antibody and Protein Purification Unit, and ³Gene Silencing Section, Office of Science and Technology Partnerships, Office of the Director, Center for Cancer Research, National Cancer Institute, NIH; ⁴Special Diagnostics Section and ⁵Molecular Signaling Section, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland; ⁶Cancer Research Institute, University of California San Francisco, San Francisco, California; ⁷Enzon Pharmaceuticals, Inc., Piscataway, New Jersey; and ⁸Translational Genomics Research Institute, Phoenix, Arizona

^* To whom correspondence should be addressed. E-mail: jw4i{at}nih.gov.

	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 pharmacogenomic/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 biomarker for patient selection. [Mol Cancer Ther 2006;5(11):2613-23]

Key Words: asparagine synthetase, asparaginase, ovarian cancer, biomarker, pharmacogenomics, RNAi

This article has been cited by other articles:

				P. L. Lorenzi, J. Llamas, M. Gunsior, L. Ozbun, W. C. Reinhold, S. Varma, H. Ji, H. Kim, A. A. Hutchinson, E. C. Kohn, et al. Asparagine synthetase is a predictive biomarker of L-asparaginase activity in ovarian cancer cell lines Mol. Cancer Ther., October 1, 2008; 7(10): 3123 - 3128. [Abstract] [Full Text] [PDF]

				P. E. Blower, J. S. Verducci, S. Lin, J. Zhou, J.-H. Chung, Z. Dai, C.-G. Liu, W. Reinhold, P. L. Lorenzi, E. P. Kaldjian, et al. MicroRNA expression profiles for the NCI-60 cancer cell panel Mol. Cancer Ther., May 1, 2007; 6(5): 1483 - 1491. [Abstract] [Full Text] [PDF]

				W. C. Reinhold, M. A. Reimers, A. K. Maunakea, S. Kim, S. Lababidi, U. Scherf, U. T. Shankavaram, M. S. Ziegler, C. Stewart, H. Kouros-Mehr, et al. Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells Mol. Cancer Ther., February 1, 2007; 6(2): 391 - 403. [Abstract] [Full Text] [PDF]