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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • CRISPR-Cas Systems
  • Carcinoma, Medullary / drug therapy
  • Carcinoma, Medullary / genetics*
  • Cell Cycle
  • Cell Line, Tumor
  • Exome
  • Female
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kidney / metabolism
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / genetics*
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasm Transplantation
  • Proteasome Endopeptidase Complex / genetics*
  • Proteasome Inhibitors / pharmacology*
  • RNA Interference
  • SMARCB1 Protein / genetics*
  • Sequence Analysis, RNA
  • Ubiquitin / chemistry
  • Whole Genome Sequencing

Substances

  • Proteasome Inhibitors
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Ubiquitin
  • Proteasome Endopeptidase Complex

Associated data

  • GEO/GSE111787
  • GEO/GSE64019
  • GEO/GSE70421
  • GEO/GSE70678
  • GEO/GSE36133
  • GEO/GSE94321
  • dbGaP/phs001800.v1.p1