Renal medullary carcinomas depend uponSMARCB1loss and are sensitive to proteasome inhibition

AbstractRenal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. Through direct-to-patient outreach, we developed genomically faithful patient-derived models of RMC. Using whole genome sequencing, we identified intronic fusion events in oneSMARCB1allele with concurrent loss of the other allele, confirming that SMARCB1 loss occurs in RMC. Biochemical and functional characterization of these RMC models revealed that RMC depends on the loss ofSMARCB1for survival and functionally resemble other cancers that harbor loss ofSMARCB1, such as malignant rhabdoid tumors or atypical teratoid rhabdoid tumors. We performed RNAi and CRISPR-Cas9 loss of function genetic screens and a small-molecule screen and identifiedUBE2Cas an essential gene in SMARCB1 deficient cancers. We found that the ubiquitin-proteasome pathway was essential for the survival of SMARCB1 deficient cancersin vitroandin vivo.Genetic or pharmacologic inhibition of this pathway leads to G2/M arrest due to constitutive accumulation of cyclin B1. These observations identify a synthetic lethal relationship that may serve as a therapeutic approach for patients with SMARCB1 deficient cancers.