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Cancer Cell. 2019 Feb 11;35(2):204-220.e9. doi: 10.1016/j.ccell.2019.01.006.

p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors.

Author information

1
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
2
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
3
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
4
Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli 80078, Italy.
5
The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032, USA.
6
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
7
Centre Hospitalier Régional et Universitaire Strasbourg, Hôpital Civil, 1 Place de L'Hôpital, Strasbourg 67091, France; Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch 67400, France.
8
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
9
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
10
Department of Pathology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA.
11
Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
12
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
13
Department of Pathology, Johns Hopkins University, 600 N. Wolfe Street/Carnegie 417, Baltimore, MD 21287, USA.
14
Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
15
Dipartimento di Patologia Generale, Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, Roma 00168, Italy.
16
Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
17
Center for Precision Environmental Health, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
18
Department of Urology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
19
Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38120, USA.
20
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
21
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: ntannir@mdanderson.org.
22
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: gdraetta@mdanderson.org.
23
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: ggenovese@mdanderson.org.

Abstract

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

KEYWORDS:

BIRC5; ER stress; MYC; SMARCB1; autophagy; embryonic mosaic GEM models; p53; proteasome inhibitors; renal medullary carcinoma; rhabdoid tumors

PMID:
30753823
DOI:
10.1016/j.ccell.2019.01.006
[Indexed for MEDLINE]
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