Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that 
respond poorly to current therapies. In this study, we screened several MRT cell 
lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to 
identify potential drug targets specific for these cancers. We discovered MDM2 
and MDM4, the canonical negative regulators of p53, as significant 
vulnerabilities. Using two compounds currently in clinical development, 
idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells 
were more sensitive than other p53 wild-type cancer cell lines to inhibition of 
MDM2 alone as well as dual inhibition of MDM2/4. These compounds caused 
significant upregulation of the p53 pathway in MRT cells, and sensitivity was 
ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of 
SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRTs, 
sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated 
apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, 
with a 5-day idasanutlin pulse causing marked regression of all xenografts, 
including durable complete responses in 50% of mice. Together, these studies 
identify a genetic connection between mutations in the SWI/SNF 
chromatin-remodeling complex and the tumor suppressor gene TP53 and provide 
preclinical evidence to support the targeting of MDM2 and MDM4 in this 
often-fatal pediatric cancer. SIGNIFICANCE: This study identifies two targets, 
MDM2 and MDM4, as vulnerabilities in a deadly pediatric cancer and provides 
preclinical evidence that compounds inhibiting these proteins have therapeutic 
potential.