Targeting the p53 pathway to treat Malignant Rhabdoid and Atypical Teratoid Rhabdoid Tumors

Abstract Rhabdoid tumors (RTs) predominantly affect young children and are among the deadliest pediatric solid tumors. Despite multimodal therapy consisting of surgery, radiation, and chemotherapy, children with these tumors have median survival of less than one year. RTs can arise throughout the body, including the central nervous system (CNS) where they are called atypical teratoid rhabdoid tumors (AT/RTs), and in extra-CNS locations such as the kidneys and other soft tissues where they are designated malignant RTs (MRTs). We previously identified MDM2 and MDM4 as therapeutic vulnerabilities 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 CNS RT tumors is unknown. Moreover, single agent therapies are prone to resistance and often show limited clinical benefit on their own. Therefore, we sought to identify combination strategies incorporating idasanutlin that would be effective in both CNS and extra-CNS RTs. Here, we show that the XPO1 inhibitor selinexor increased nuclear retention of p53 and potentiated idasanutlin-induced p53 pathway activation and cytotoxicity in AT/RT and MRT cell lines in vitro. Importantly, combination therapy limited acquired resistance through TP53 mutation. In vivo, combination therapy was well-tolerated, reduced tumor burden, and increased survival in orthotopic models of both AT/RT and MRT. Our results demonstrate that combining idasanutlin with selinexor is a promising therapeutic strategy for children with rhabdoid tumors.