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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 12, 2019
- Source ID
- 10.7554/elife.44161
Entities
People
- Abeer Sayeed
- Abigail Ward
- Adam Tracy
- Alanna J Church
- Andrew L Hong
- Barbara Van Hare
- Brian D Crompton
- Brian Mcsteen
- Bryan D Kynnap
- Catherine M Clinton
- Charles Wm Roberts
- Cigall Kadoch
- Cora Connor
- David E Root
- David Sandak
- Elizabeth A Mullen
- Gabriel J. Sandoval
- Guillaume Kugener
- Jeremiah A. Wala
- Jesse S Boehm
- Ji Li
- Katherine A. Janeway
- Katherine M Labella
- Keith L Ligon
- Mahmhoud Ghandi
- Michelle Tillgren
- Mihir B. Doshi
- Ole Gjoerup
- Paul A Clemons
- Paula Keskula
- Prafulla C Gokhale
- Pratiti Bandopadhayay
- Rameen Beroukhim
- Rebecca Deasy
- Stuart Schreiber
- Susan N Chi
- Thomas P Howard
- William C Hahn
- Won-jun Kim
- Xiaoping Yang
- Yuen-yi Tseng
Organizations
- Alex's Lemonade Stand Foundation
- American Association for Cancer Research
- American Cancer Society
- Boston Children's Hospital
- Brigham and Women's Hospital
- Broad Institute
- CureSearch for Children's Cancer
- Dana–Farber Cancer Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Cancer Institute
- National Institute of General Medical Sciences
- St. Jude Children's Research Hospital
- United States Department of Defense