Asparagine synthetase is a biomarker of L-asparaginase activity in multiple cancer cell types

B28 Molecular profiling can identify biomarkers that predict response to therapy in cell lines, in animal models, and in the clinic. We recently used molecular profiling and RNAi analysis to show that asparagine synthetase (ASNS) is a causal biomarker for activity of the anti-leukemia enzyme-drug L-asparaginase (L-ASP) in ovarian lines of the NCI-60 panel. Although leukemic and ovarian were the only subpanels of the NCI-60 to exhibit strong L-ASP/ASNS correlations, we nevertheless hypothesized that modulation of ASNS expression by RNAi would reveal a causal relationship between ASNS expression and L-ASP efficacy in other cancer cell types as well. In support of that hypothesis, we have now found that RNAi-mediated silencing of ASNS results in a 3- to 10,000-fold potentiation of L-ASP activity in breast, colon, CNS, prostate, melanoma, and renal cancers lines from the NCI-60 set. Interestingly, we also find that the mechanism of L-ASP potentiation by RNAi involves more than just a leftward shift of the L-ASP dose-response curve; RNAi also suppresses a rightward shift of the dose-response curve caused by ASNS up-regulation following L-ASP treatment. Those findings prompted us to investigate at the RNA and protein levels how well ASNS expression can predict L-ASP activity across multiple cancer types in the NCI-60. The most striking result was that baseline ASNS protein levels yield a strong correlation with L-ASP efficacy (r = -0.64; p = 0.012, one-tailed). These findings provide rationale for clinical evaluation of ASNS protein expression as a predictive biomarker of L-ASP efficacy across multiple cancer types.