Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells.
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.
Lorenzi
Philip L
PL
Genomics and Bioinformatics Group, Room 5056B, 37 Convent Drive, Bethesda, MD 20892, USA. jw4i@nih.gov
Reinhold
William C
WC
Rudelius
Martina
M
Gunsior
Michele
M
Shankavaram
Uma
U
Bussey
Kimberly J
KJ
Scherf
Uwe
U
Eichler
Gabriel S
GS
Martin
Scott E
SE
Chin
Koei
K
Gray
Joe W
JW
Kohn
Elise C
EC
Horak
Ivan D
ID
Von Hoff
Daniel D
DD
Raffeld
Mark
M
Goldsmith
Paul K
PK
Caplen
Natasha J
NJ
Weinstein
John N
JN
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
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase