Targeting the p53 Pathway to Treat Atypical Teratoid Rhabdoid Tumors

Background Rhabdoid tumors (RTs) are rare aggressive pediatric cancers that can arise throughout the body, including in the central nervous system (CNS) where they are called atypical teratoid rhabdoid tumors (ATRTs), and in extra-CNS locations such as kidneys and other soft tissues where they are designated as malignant rhabdoid tumors (MRTs). We previously identified MDM2 as a therapeutic vulnerability in RTs and showed that treatment with the MDM2 inhibitor idasanutlin increased survival in mice bearing MRT xenografts. However, the therapeutic potential of idasanutlin in ATRTs, where the blood-brain barrier limits drug access, was unknown. We hypothesized that combining idasanutlin with selinexor, a CNS penetrant XPO1 inhibitor, would potentiate p53-mediated activation and increase therapeutic response in vivo. Methods We characterized XPO1 and the p53 pathway in RT cell lines and patient samples using whole genome sequencing, evaluated the pharmacodynamic consequence of treatment with idasanutlin and/or selinexor using immunoblot and quantitative proteomics, and assessed the effect of each agent and the combination on cell viability in vitro and in orthotopic xenograft models in vivo. Mechanisms of therapeutic resistance were identified in ATRT cells subject to long-term cell culture experiments under escalating drug pressure. Results Selinexor potentiated idasanutlin-induced p53 pathway activation but also caused p53-independent cytotoxicity in ATRT cells. In vivo combination therapy was well-tolerated, reduced tumor burden, and increased survival. The BCL-2 family of proteins were identified as key modulators of intrinsic and acquired resistance. Conclusions Combining MDM2 inhibitors and XPO1 inhibitors is a promising therapeutic strategy for treating children with ATRT.