Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

Abstract

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one <i>SMARCB1</i> allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of <i>SMARCB1</i> for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor <i>SMARCB1</i> loss, which also require expression of the E2 ubiquitin-conjugating enzyme, <i>UBE2C</i>. Our studies identify a synthetic lethal relationship between <i>SMARCB1</i>-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.