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Elife. 2019 Mar 12;8. pii: e44161. doi: 10.7554/eLife.44161.

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition.

Author information

1
Boston Children's Hospital, Boston, United States.
2
Dana-Farber Cancer Institute, Boston, United States.
3
Broad Institute of Harvard and MIT, Cambridge, United States.
4
Rare Cancer Research Foundation, Durham, United States.
5
RMC Support, North Charleston, United States.
6
St. Jude Children's Research Hospital, Memphis, United States.
7
Brigham and Women's Hospital, Boston, 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.

KEYWORDS:

MLN2238; SMARCB1; cancer biology; cell cycle; human; human biology; medicine; renal medullary carcinoma; ubiquitin-proteasome system

Conflict of interest statement

AH, YT, JW, WK, BK, MD, GK, GS, TH, JL, XY, MT, MG, AS, RD, AW, BM, KL, PK, AT, CC, CC, AC, BC, KJ, BV, DS, OG, SS, DR, PG, SC, EM, CR, KL, JB No competing interests declared, PB, RB is a consultant for Novartis (Cambridge, MA), PC is an adviser for Pfizer, Inc (Groton, CT), CK 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 CK is also found at: http://www.kadochlab.org, WH 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

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