You are here

Elife DOI:10.7554/eLife.44161

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

Publication TypeJournal Article
Year of Publication2019
AuthorsHong, AL, Tseng, Y-Y, Wala, JA, Kim, W-J, Kynnap, BD, Doshi, MB, Kugener, G, Sandoval, GJ, Howard, TP, Li, J, Yang, X, Tillgren, M, Ghandi, M, Sayeed, A, Deasy, R, Ward, A, McSteen, B, Labella, KM, Keskula, P, Tracy, A, Connor, C, Clinton, CM, Church, AJ, Crompton, BD, Janeway, KA, Van Hare, B, Sandak, D, Gjoerup, O, Bandopadhayay, P, Clemons, PA, Schreiber, SL, Root, DE, Gokhale, PC, Chi, SN, Mullen, EA, Roberts, CWm, Kadoch, C, Beroukhim, R, Ligon, KL, Boehm, JS, Hahn, WC
JournalElife
Volume8
Date Published2019 Mar 12
ISSN2050-084X
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 allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of 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 loss, which also require expression of the E2 ubiquitin-conjugating enzyme, . Our studies identify a synthetic lethal relationship between -deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.

DOI10.7554/eLife.44161
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30860482?dopt=Abstract

Alternate JournalElife
PubMed ID30860482
PubMed Central IDPMC6436895
Grant ListYoung Investigator Award / / Alex's Lemonade Stand Foundation for Childhood Cancer /
14-40-31-HONG / / American Association for Cancer Research /
132943-MRSG-18-202-01-TBG / / American Cancer Society /
OFD BTREC CDA / / Boston Children's Hospital /
328545 / / CureSearch for Children's Cancer /
Wong Family Award / / Dana-Farber Cancer Institute /
K12 HD052896 / / Eunice Kennedy Shriver National Institute of Child Health and Human Development /
U01 CA176058 / / National Cancer Institute /
U01 CA217848 / / National Cancer Institute /
P50 CA101942 / / National Cancer Institute /
T32 GM007753 / / National Institute of General Medical Sciences /
T32 GM007226 / / National Institute of General Medical Sciences /
W81XWH-15-1-0659 / / U.S. Department of Defense /