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

• Published in: Molecular cancer therapeutics Vol. 5; no. 11; pp. 2613 - 2623
• Main Authors: Lorenzi, Philip L, Reinhold, William C, Rudelius, Martina, Gunsior, Michele, Shankavaram, Uma, Bussey, Kimberly J, Scherf, Uwe, Eichler, Gabriel S, Martin, Scott E, Chin, Koei, Gray, Joe W, Kohn, Elise C, Horak, Ivan D, Von Hoff, Daniel D, Raffeld, Mark, Goldsmith, Paul K, Caplen, Natasha J, Weinstein, John N
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-11-2006
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; asparaginase; Asparaginase - pharmacology; Asparaginase - toxicity; asparagine synthetase; Aspartate-Ammonia Ligase - genetics; Aspartate-Ammonia Ligase - metabolism; biomarker; Biomarkers, Tumor - metabolism; Cell Line, Tumor; DNA, Neoplasm - metabolism; Drug Resistance, Multiple; Female; Gene Expression Profiling; Humans; Oligonucleotide Array Sequence Analysis; ovarian cancer; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - pathology; pharmacogenomics; RNA Interference; RNA, Messenger - metabolism; RNAi; Time Factors
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-06-0447

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]