Optimizing mdm2 inhibition for the treatment of glioblastoma

Abstract Over 60% of glioblastomas retain wild-type p53, resulting in potential susceptibility to MDM2 inhibitors. These molecules disrupt the interaction between p53 and its negative regulator MDM2, allowing downstream pathway signaling and cell fate decisions including growth inhibition and death resulting from cellular stress. We have analyzed clinical samples from 10 patients newly diagnosed with glioblastoma multiforme (GBM) and treated with the MDM2 inhibitor KRT-232. We detected upregulation of CDKN1A transcript (a target of p53) in all p53 wild-type tumors (8 of 10), but not in p53-mutant tumors (2 of 10). In patient-derived cell lines, treatment with KRT-232 at the clinically detected concentration was only sufficient to stall tumor growth. Cell death via apoptosis can be achieved when MDM2 inhibition is combined with the chemotherapeutic agent temozolomide. As the effects and resistance mechanisms of MDM2 inhibition remain poorly understood in GBM, we have additionally performed genomic and transcriptomic analyses in patient-derived cell lines to better characterize sensitive tumors and identify putative biomarkers of drug response. Dose response curves and growth assays showed that tumors with inactivating p53 mutations are highly resistant to treatment, but those that retain wild-type p53 exhibit various degrees of drug sensitivity. This suggests that other factors, in addition to p53 mutational status, mediate response to MDM2 inhibition in gliomas. Transcriptional analyses of patient samples following drug treatment suggest that cell division, chromatin reorganization, cell differentiation state and immune response programs become deregulated under MDM2 inhibition and in the absence of p53-inactivating mutations.