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Renal Medullary Carcinomas Depend Upon SMARCB1 Loss and Are Sensitive to 2 Proteasome Inhibition 3 4 5 Andrew L bioRxiv preprint doi: https://doi.org/10.1101/487579; this version posted December 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to 2 proteasome inhibition 3 4 5 Andrew L. Hong1,2,3, Yuen-Yi Tseng3, Jeremiah Wala3, Won Jun Kim2, Bryan D. Kynnap2, 6 Mihir B. Doshi3, Guillaume Kugener3, Gabriel J. Sandoval2,3, Thomas P. Howard2, Ji Li2, 7 Xiaoping Yang3, Michelle Tillgren2, Mahmoud Ghandi3, Abeer Sayeed3, Rebecca Deasy3, 8 Abigail Ward1,2, Brian McSteen4, Katherine M. Labella2, Paula Keskula3, Adam Tracy3, 9 Cora Connor5, Catherine M. Clinton1,2, Alanna J. Church1, Brian D. Crompton1,2,3, 10 Katherine A. Janeway1,2, Barbara Van Hare4, David Sandak4, Ole Gjoerup2, 11 Pratiti Bandopadhayay1,2,3, Paul A. Clemons3, Stuart L. Schreiber3, David E. Root3, 12 Prafulla C. Gokhale2, Susan N. Chi1,2, Elizabeth A. Mullen1,2, Charles W. M. Roberts6, 13 Cigall Kadoch2,3, Rameen Beroukhim2,3,7, Keith L. Ligon2,3,7, Jesse S. Boehm3, 14 William C. Hahn2,3,7* 15 Affiliations: 16 1Boston Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA 17 2Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts, 02215 USA 18 3Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts, 02142 USA 19 4Rare Cancer Research Foundation, 112 S. Duke Street, Suite 101, Durham, NC 27701 USA 20 5RMC Support, P.O. Box 73156, North Charleston, S.C. 29415 USA 21 6St. Jude Children’s Research Hospital, St. Jude Children’s Research Hospital, 262 Danny Thomas 22 Place, Memphis, Tennessee 38120, USA 23 7Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts, 02115 USA 24 1 bioRxiv preprint doi: https://doi.org/10.1101/487579; this version posted December 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 25 *To whom correspondence should be addressed: 26 William C. Hahn, M.D., Ph.D. 27 Department of Medical Oncology 28 Dana-Farber Cancer Institute 29 450 Brookline Avenue, Dana 1538 30 Boston, MA 02215 31 617-632-2641 (phone) 32 [email protected] 33 34 35 2 bioRxiv preprint doi: https://doi.org/10.1101/487579; this version posted December 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 36 Abstract: 37 Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African 38 descent with sickle cell trait. Through direct-to-patient outreach, we developed genomically 39 faithful patient-derived models of RMC. Using whole genome sequencing, we identified intronic 40 fusion events in one SMARCB1 allele with concurrent loss of the other allele, confirming that 41 SMARCB1 loss occurs in RMC. Biochemical and functional characterization of these RMC 42 models revealed that RMC depends on the loss of SMARCB1 for survival and functionally 43 resemble other cancers that harbor loss of SMARCB1, such as malignant rhabdoid tumors or 44 atypical teratoid rhabdoid tumors. We performed RNAi and CRISPR-Cas9 loss of function genetic 45 screens and a small-molecule screen and identified UBE2C as an essential gene in SMARCB1 46 deficient cancers. We found that the ubiquitin-proteasome pathway was essential for the survival 47 of SMARCB1 deficient cancers in vitro and in vivo. Genetic or pharmacologic inhibition of this 48 pathway leads to G2/M arrest due to constitutive accumulation of cyclin B1. These observations 49 identify a synthetic lethal relationship that may serve as a therapeutic approach for patients with 50 SMARCB1 deficient cancers. 51 52 3 bioRxiv preprint doi: https://doi.org/10.1101/487579; this version posted December 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 53 Introduction 54 Renal medullary carcinoma (RMC) was first identified in 1995 and is described as the 55 seventh nephropathy of sickle cell disease (Jr et al., 1995). RMC is a rare cancer that occurs 56 primarily in patients of African descent that carry sickle cell trait and presents during adolescence 57 with symptoms of abdominal pain, hematuria, weight loss and widely metastatic disease. Due to 58 the aggressive behavior of this disease and the small numbers of patients, no standard of care 59 exists, and patients are generally treated with therapies including nephrectomy, chemotherapy and 60 radiation therapy. Despite, this aggressive regimen, the mean overall survival rate is only 6-8 61 months (Alvarez et al., 2015; Beckermann et al., 2017; Ezekian et al., 2017; Iacovelli et al., 2015). 62 Gene expression of tumor samples from patients with RMC indicates that this entity is distinct 63 from renal cell carcinomas and urothelial carcinomas (Swartz et al., 2002; Yang et al., 2004). 64 Recent studies have identified that SMARCB1 is lost at the protein level in RMC (Cheng 65 et al., 2008). SMARCB1 is a tumor suppressor and core member of the SWI/SNF complex 66 implicated in malignant rhabdoid tumors (MRT) and atypical teratoid rhabdoid tumors 67 (ATRT)(Roberts et al., 2002). MRTs and ATRTs harbor few somatic genetic alterations and occur 68 in young children (Gröbner et al., 2018; Lawrence et al., 2013; Lee et al., 2012; Ma et al., 2018). 69 In contrast to MRTs and ATRTs, where there is biallelic loss of SMARCB1 in the genome (Chun 70 et al., 2016; Torchia et al., 2016), in RMCs, fusion events in SMARCB1 have been identified in 4 71 of 5 patients (Calderaro et al., 2016) and 8 of 10 patients (Carlo et al., 2017) using whole exome 72 sequencing (WES), fluorescence in situ hybridization (FISH), array comparative genomic 73 hybridization (CGH), and RNA-sequencing. An unresolved question is whether these cancers 74 depend upon loss of this tumor suppressor, since deletion of SMARCB1 in mice does not lead to 75 renal cancers (Roberts et al., 2002). 4 bioRxiv preprint doi: https://doi.org/10.1101/487579; this version posted December 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 76 To date, limited tissue from these patients has prevented full characterization of RMC. 77 Here, we characterized new patient-derived cell lines developed from samples following 78 neoadjuvant therapy and at relapse. These cell lines have allowed us to functionally demonstrate 79 dependence of RMC on loss of SMARCB1 for survival and to uncover the proteasome as a core 80 druggable vulnerability. 81 82 Results 83 Derivation and genomic characterization of RMC models 84 We developed models from two patients with a diagnosis of RMC (Methods). For the first 85 patient, we obtained the primary tissue from our local institution at the time of the initial 86 nephrectomy. We generated a short-term culture normal cell line, CLF_PEDS0005_N, and a tumor 87 cell line, CLF_PEDS0005_T1 (Supp Fig. 1A). In addition, we obtained fluid from a thoracentesis 88 performed when the patient relapsed 8 months into therapy. We isolated two cell lines that grew 89 either as an adherent monolayer, CLF_PEDS0005_T2A, or in suspension, CLF_PEDS0005_T2B. 90 Each of these tumor cell lines expressed the epithelial marker, CAM5.2, and lacked expression of 91 SMARCB1 similar to that observed in the primary tumor (Supp Fig. 1B). For the second patient, 92 we partnered with the Rare Cancer Research Foundation and obtained samples through a direct- 93 to-patient portal (www.pattern.org). The primary tumor tissue from the second patient was 94 obtained at the time of the initial nephrectomy. From this sample, we generated the tumor cell line, 95 CLF_PEDS9001_T1. Both patients received 4-8 weeks neoadjuvant chemotherapy prior to their 96 nephrectomy. 97 Prior studies have identified deletion of one allele of SMARCB1 along with fusion events 98 in SMARCB1 in RMC patients (Calderaro et al., 2016; Carlo et al., 2017). Specifically, one study 5 bioRxiv preprint doi: https://doi.org/10.1101/487579; this version posted December 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 99 identified SMARCB1 fusion events in 8 of 10 patients utilizing FISH, while another study 100 identified fusion events in 4 of 5 patients utilizing a combination of FISH, RNA-sequencing and 101 Sanger sequencing. We performed WES (CLF_PEDS0005) or PCR-free whole genome 102 sequencing (WGS; CLF_PEDS9001) on the primary kidney tumor tissue. In both patients, we 103 found tumor purity was <20% and confirmed the presence of sickle cell trait (Supp Fig. 1C). This 104 low tumor purity is attributable to the stromal desmoplasia seen in RMC (Swartz et al., 2002). 105 Furthermore, we failed to identify homozygous or heterozygous deletions or mutations of 106 SMARCB1 due to the low tumor purity. 107 We performed WES on the normal cell line (CLF_PEDS0005_N) or whole blood 108 (CLF_PEDS9001) and compared it to the primary tumor cell lines (CLF_PEDS0005_T1 and 109 CLF_PEDS9001_T) and metastatic cell lines (CLF_PEDS0005_T2A and CLF_PEDS0005_T2B). 110 We used the Genome Analysis Toolkit (GATK) v4.0.4.0 for variant discovery and copy number 111 analyses (Methods) (McKenna et al., 2010) and found a low mutation frequency (1-3 112 mutations/mb; Fig. 1A) in the tumor cell lines similar to that of other pediatric cancers and cell 113 lines such as MRT, ATRT and Ewing sarcoma (Cibulskis et al., 2013; Johann et al., 2016; Wala 114 et al., 2018).
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