Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition
- Dana-Farber Cancer Institute, United States
- Broad Institute of Harvard and MIT, United States
- Rare Cancer Research Foundation, United States
- RMC Support, United States
- Boston Children's Hospital, United States
- St Jude Children's Research Hospital, United States
- Dana-Farber Cancer Institue, United States
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.
Data availability
Data and materials availability: Noted plasmids in the text are available through Addgene or the Genomics Perturbations Platform at the Broad Institute of Harvard and MIT. CLF_PEDS0005_T1, CLF_PEDS0005_T2B, CLF_PEDS0005_T2A and CLF_PEDS9001_T1 cell lines are available through the Cancer Cell Line Factory at the Broad Institute of Harvard and MIT. Sequencing data reported in this paper (whole-genome sequencing and whole-exome sequencing) has been deposited in the database of Genotypes and Phenotypes (dbGaP) and GEO GSE111787.
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Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibitionNCBI Gene Expression Omnibus, GSE111787.
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Mouse Smarcb1-deficient models recapitulate subtypes of human rhabdoid tumors.NCBI Gene Expression Omnibus, GSE64019.
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SMARCB1-deficient rhaboid tumors of the kidney and renal medullary carcinomas.NCBI Gene Expression Omnibus, GSE70421.
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Gene expression data from ATRT tumor samplesNCBI Gene Expression Omnibus, GSE70678.
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Expression data from the Cancer Cell Line Encyclopedia (CCLE)NCBI Gene Expression Omnibus, GSE36133.
Article and author information
Author details
Funding
National Cancer Institute (U01 CA176058)
- William C Hahn
Wong Family Award
- Andrew L Hong
American Cancer Society (132943-MRSG-18-202-01-TBG)
- Andrew L Hong
National Cancer Institute (U01 CA217848)
- Stuart L Schreiber
National Institute of General Medical Sciences (T32 GM007753)
- Thomas P Howard
National Institute of General Medical Sciences (T32 GM007226)
- Thomas P Howard
Boston Children's Hospital (OFD BTREC CDA)
- Andrew L Hong
U.S. Department of Defense (W81XWH-15-1-0659)
- Gabriel J Sandoval
National Cancer Institute (P50 CA101942)
- Andrew L Hong
Katie Moore Foundation
- Jesse S Boehm
Merkin Family Foundation
- Jesse S Boehm
American Association for Cancer Research (14-40-31-HONG)
- Andrew L Hong
CureSearch for Children's Cancer (328545)
- Andrew L Hong
Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12 HD052896)
- Andrew L Hong
Alex's Lemonade Stand Foundation for Childhood Cancer (Young Investigator Award)
- Andrew L Hong
Cure AT/RT
- Andrew L Hong
- Susan N Chi
Team Path to Cure
- Andrew L Hong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This research protocol (04-111) has been reviewed and approved by the Dana-Farber Cancer Institute's Animal Care and Use Committee (IACUC), in compliance with the Animal Welfare Act and the Office of Laboratory Welfare (OLAW) of the National Institutes of Health (NIH).
Human subjects: Patients assented and / or families consented to Dana-Farber Cancer Institute IRB approved protocols: 11-104, 16-031.
Reviewing Editor
- Ross L Levine, Memorial Sloan Kettering Cancer Center, United States
Publication history
- Received: December 5, 2018
- Accepted: March 3, 2019
- Accepted Manuscript published: March 12, 2019 (version 1)
- Version of Record published: March 27, 2019 (version 2)
Copyright
© 2019, Hong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition
eLife 8:e44161.
https://doi.org/10.7554/eLife.44161
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