TY - JOUR TI - Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition AU - Hong, Andrew L AU - Tseng, Yuen-Yi AU - Wala, Jeremiah A AU - Kim, Won-Jun AU - Kynnap, Bryan D AU - Doshi, Mihir B AU - Kugener, Guillaume AU - Sandoval, Gabriel J AU - Howard, Thomas P AU - Li, Ji AU - Yang, Xiaoping AU - Tillgren, Michelle AU - Ghandi, Mahmhoud AU - Sayeed, Abeer AU - Deasy, Rebecca AU - Ward, Abigail AU - McSteen, Brian AU - Labella, Katherine M AU - Keskula, Paula AU - Tracy, Adam AU - Connor, Cora AU - Clinton, Catherine M AU - Church, Alanna J AU - Crompton, Brian D AU - Janeway, Katherine A AU - Van Hare, Barbara AU - Sandak, David AU - Gjoerup, Ole AU - Bandopadhayay, Pratiti AU - Clemons, Paul A AU - Schreiber, Stuart L AU - Root, David E AU - Gokhale, Prafulla C AU - Chi, Susan N AU - Mullen, Elizabeth A AU - Roberts, Charles WM AU - Kadoch, Cigall AU - Beroukhim, Rameen AU - Ligon, Keith L AU - Boehm, Jesse S AU - Hahn, William C A2 - Settleman, Jeffrey A2 - Levine, Ross L A2 - Levine, Ross L A2 - Brugarolas, James A2 - Abate-Shen, Cory VL - 8 PY - 2019 DA - 2019/03/12 SP - e44161 C1 - eLife 2019;8:e44161 DO - 10.7554/eLife.44161 UR - https://doi.org/10.7554/eLife.44161 AB - 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. KW - renal medullary carcinoma KW - SMARCB1 KW - MLN2238 KW - ubiquitin-proteasome system KW - cell cycle JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -