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

Andrew L Hong ,Mahmhoud Ghandi,David Sandak,Rebecca Deasy,Michelle Tillgren,Cigall Kadoch,Brian Mcsteen,Barbara Van Hare,Paula Keskula,Ole Gjoerup,Rameen Beroukhim,Won-Jun Kim,Adam Tracy,Guillaume Kugener,Abigail Ward,Xiaoping Yang,Ji Li,Cora Connor,Abeer Sayeed,Pratiti Bandopadhayay,Elizabeth Mullen ,Mihir B Doshi ,Jeremiah A Wala ,N Susan ,Prafulla C Gokhale ,Brian D Crompton ,Stuart L Schreiber ,David E Root ,Paul A Clemons ,Jesse S Boehm ,Katherine A Janeway ,Katherine Labella ,Charles W.m Roberts ,Catherine Clinton ,Keith L Ligon ,Gabriel J Sandoval ,Alanna J Church ,Bryan D Kynnap ,Thomas P Howard ,Yuen‐Yi Tseng ,William C Hahn

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.

Highlights

Renal medullary carcinoma (RMC) was first identified in 1995 and is described as the seventh nephropathy of sickle cell disease (Davis et al, 1995)
For CLF_PEDS0005_T1, we found a large deletion between BCR and MYH9 which is predicted to lead to loss of one allele of SMARCB1 (Figure 1c) along with a balanced translocation between intron 1 of SMARCB1 to the intron region following the C-terminal end of C1orf116, yielding a non-functional allele (Figure 1d and Supplementary file 3)
Our integrated RNAi, CRISPR-Cas9 and small molecule screens identified that our RMC models required expression of PLK1 and CDK1, genes involved in G2/M, for survival (Figure 3a–b), and prior studies have identified that inhibition of PLK1 in atypical teratoid rhabdoid tumors (ATRTs) or malignant rhabdoid tumors (MRTs) cells leads to arrest in G2/M (Alimova et al, 2017; Morozov et al, 2007)

Summary

Introduction

Renal medullary carcinoma (RMC) was first identified in 1995 and is described as the seventh nephropathy of sickle cell disease (Davis et al, 1995). Cancer Biology Human Biology and Medicine eLife digest Renal medullary carcinoma (RMC for short) is a rare type of kidney cancer that affects teenagers and young adults. These patients are usually of African descent and carry one of the two genetic changes that cause sickle cell anemia. Hong et al worked with patients to develop new lines of cells that can be used to study RMC in the laboratory. Drugs and genetic reagents that reduced the activity of the proteasome – the structure inside cells that gets rid of old or unwanted proteins – caused the RMC cells to die These proteasome inhibitor drugs killed other kinds of cancer cells with SMARCB1 mutations. We demonstrate that RMC depends on loss of SMARCB1 for survival and, through integrated genetic and pharmacologic studies, we uncover the proteasome as a core druggable vulnerability in RMC and other SMARCB1-deficient cancers

Results

UBE2C SMARCB1

Discussion

Materials and methods