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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Andrew L Hong

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0374-1667
  2. Yuen-Yi Tseng

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Jeremiah A Wala

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Won-Jun Kim

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Bryan D Kynnap

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  6. Mihir B Doshi

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. Guillaume Kugener

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  8. Gabriel J Sandoval

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  9. Thomas P Howard

    Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  10. Ji Li

    Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Xiaoping Yang

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  12. Michelle Tillgren

    Belfer Institute, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  13. Mahmhoud Ghandi

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  14. Abeer Sayeed

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  15. Rebecca Deasy

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  16. Abigail Ward

    Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  17. Brian McSteen

    Rare Cancer Research Foundation, Durham, United States
    Competing interests
    No competing interests declared.
  18. Katherine M Labella

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  19. Paula Keskula

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  20. Adam Tracy

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  21. Cora Connor

    RMC Support, North Charleston, United States
    Competing interests
    No competing interests declared.
  22. Catherine M Clinton

    Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  23. Alanna J Church

    Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  24. Brian D Crompton

    Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  25. Katherine A Janeway

    Belfer Institute, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  26. Barbara Van Hare

    Rare Cancer Research Foundation, Durham, United States
    Competing interests
    No competing interests declared.
  27. David Sandak

    Rare Cancer Research Foundation, Durham, United States
    Competing interests
    No competing interests declared.
  28. Ole Gjoerup

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  29. Pratiti Bandopadhayay

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Pratiti Bandopadhayay, is a consultant for Novartis (Cambridge, MA).
  30. Paul A Clemons

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    Paul A Clemons, is an adviser for Pfizer, Inc. (Groton, CT).
  31. Stuart L Schreiber

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  32. David E Root

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  33. Prafulla C Gokhale

    Belfer Institute, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  34. Susan N Chi

    Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  35. Elizabeth A Mullen

    Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  36. Charles WM Roberts

    St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    No competing interests declared.
  37. Cigall Kadoch

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Cigall Kadoch, is a Scientific Founder, member of the Board of Director, Scientific Advisory Board member, Shareholder, and Consultant for Foghorn Therapeutics, Inc. (Cambridge, MA). Disclosure information for C.K. is also found at: http://www.kadochlab.org.
  38. Rameen Beroukhim

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Rameen Beroukhim, is a consultant for Novartis (Cambridge, MA).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6303-3609
  39. Keith L Ligon

    Pathology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    No competing interests declared.
  40. Jesse S Boehm

    Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6795-6336
  41. William C Hahn

    Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    For correspondence
    william_hahn@dfci.harvard.edu
    Competing interests
    William C Hahn, is a consultant for Thermo Fisher, Aju IB, MPM Capital and Paraxel. W.C.H. is a founder and shareholder and serves on the scientific advisory board of KSQ Therapeutics.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-9791

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.

Reviewing Editor

  1. Ross L Levine, Memorial Sloan Kettering Cancer Center, United States

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.

Version history

  1. Received: December 5, 2018
  2. Accepted: March 3, 2019
  3. Accepted Manuscript published: March 12, 2019 (version 1)
  4. 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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  1. Andrew L Hong
  2. Yuen-Yi Tseng
  3. Jeremiah A Wala
  4. Won-Jun Kim
  5. Bryan D Kynnap
  6. Mihir B Doshi
  7. Guillaume Kugener
  8. Gabriel J Sandoval
  9. Thomas P Howard
  10. Ji Li
  11. Xiaoping Yang
  12. Michelle Tillgren
  13. Mahmhoud Ghandi
  14. Abeer Sayeed
  15. Rebecca Deasy
  16. Abigail Ward
  17. Brian McSteen
  18. Katherine M Labella
  19. Paula Keskula
  20. Adam Tracy
  21. Cora Connor
  22. Catherine M Clinton
  23. Alanna J Church
  24. Brian D Crompton
  25. Katherine A Janeway
  26. Barbara Van Hare
  27. David Sandak
  28. Ole Gjoerup
  29. Pratiti Bandopadhayay
  30. Paul A Clemons
  31. Stuart L Schreiber
  32. David E Root
  33. Prafulla C Gokhale
  34. Susan N Chi
  35. Elizabeth A Mullen
  36. Charles WM Roberts
  37. Cigall Kadoch
  38. Rameen Beroukhim
  39. Keith L Ligon
  40. Jesse S Boehm
  41. William C Hahn
(2019)
Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition
eLife 8:e44161.
https://doi.org/10.7554/eLife.44161

Share this article

https://doi.org/10.7554/eLife.44161

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