title: Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells.
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.
authors.affiliation: Genomics and Bioinformatics Group, Room 5056B, 37 Convent Drive, Bethesda, MD 20892, USA. jw4i@nih.gov
authors.forename: Philip L
authors.initials: PL
authors.lastname: Lorenzi
authors.forename: William C
authors.initials: WC
authors.lastname: Reinhold
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.forename: Michele
authors.initials: M
authors.lastname: Gunsior
authors.forename: Uma
authors.initials: U
authors.lastname: Shankavaram
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Bussey
authors.forename: Uwe
authors.initials: U
authors.lastname: Scherf
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Eichler
authors.forename: Scott E
authors.initials: SE
authors.lastname: Martin
authors.forename: Koei
authors.initials: K
authors.lastname: Chin
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Horak
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Paul K
authors.initials: PK
authors.lastname: Goldsmith
authors.forename: Natasha J
authors.initials: NJ
authors.lastname: Caplen
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001215:Asparaginase / Q000494:pharmacology* / Q000633:toxicity; D001217:Aspartate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase