BIOM-45. DETERMINANTS OF GBM VULNERABILITY TO INHIBITORS OF NEDD8 ACTIVATING ENZYME (NAE)

Abstract

Abstract Advancing new therapeutics to FDA approval for GBM is hampered by intra- and inter-tumoral heterogeneity. Design of clinical trials to enroll patients likely to respond to a new treatment seems critical to build the arsenal of agents against this disease. Neddylation is a protein modification pathway aligned to protein degradation and cytological localization within the ubiquitin/proteasome system. Components of the neddylation pathway are frequently overexpressed or hyperactivated in GBM, and whose upregulation has been associated with glioma progression and worse survival. Among glioblastoma cell lines and patient-derived stem cells, subsets were found to be selectively susceptible to NAE inhibitors. We previously showed that PTEN signaling, DNA replication, and chromatin instability pathways are the most significant differentiators between MLN4924 sensitive vs. non-sensitive models. To test a candidate molecular “signature of vulnerability”, two subsets of PDX models (PTEN wildtype and PTEN del or mutated) were treated with a panel of 3 NAE inhibitors. 5 GBM PTENwt models were shown vulnerable to MLN4924 and TAS4464 with average EC50 values 5-10 folds lower than 6 PTENmt/del models. CDC activity was greater against PTENwt, but only 2-fold different vs PTENmt/del. Transcriptomic data mining uncovered additional determinants of response to NAE inhibitors. To disclose the relationship between constitutive expression of three gene sets: DNA Replication Fork Progressing, Replication Fork Protection, and Replication Fork Protection Complex, we found that the genes involved in these are significantly under expressed in PTENmt models when comparing to PTENwt models. The molecular determinants of drug response to NAE inhibitors will be further verified in the extended preclinical models and lead to a patient-enrollment “signature of vulnerability” to increase the likelihood of demonstrating therapeutic efficacy in the early stage of clinical trials.