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

• Main Authors: Andrew L Hong, Yuen-Yi Tseng, Jeremiah A Wala, Won-Jun Kim, Bryan D Kynnap, Mihir B Doshi, Guillaume Kugener, Gabriel J Sandoval, Thomas P Howard, Ji Li, Xiaoping Yang, Michelle Tillgren, Mahmhoud Ghandi, Abeer Sayeed, Rebecca Deasy, Abigail Ward, Brian McSteen, Katherine M Labella, Paula Keskula, Adam Tracy, Cora Connor, Catherine M Clinton, Alanna J Church, Brian D Crompton, Katherine A Janeway, Barbara Van Hare, David Sandak, Ole Gjoerup, Pratiti Bandopadhayay, Paul A Clemons, Stuart L Schreiber, David E Root, Prafulla C Gokhale, Susan N Chi, Elizabeth A Mullen, Charles WM Roberts, Cigall Kadoch, Rameen Beroukhim, Keith L Ligon, Jesse S Boehm, William C Hahn
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2019-03-01
• Series: eLife
• Subjects: renal medullary carcinoma; SMARCB1; MLN2238; ubiquitin-proteasome system; cell cycle
• Online Access: https://elifesciences.org/articles/44161
• ISSN: 2050-084X

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 SMARCB1 allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of SMARCB1 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 SMARCB1 loss, which also require expression of the E2 ubiquitin-conjugating enzyme, UBE2C. Our studies identify a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.