| Literature DB >> 30753823 |
Alessandro Carugo1, Rosalba Minelli2, Luigi Sapio2, Melinda Soeung2, Federica Carbone2, Frederick S Robinson1, James Tepper2, Ziheng Chen2, Sara Lovisa3, Maria Svelto4, Samirkumar Amin5, Sanjana Srinivasan6, Edoardo Del Poggetto2, Sara Loponte2, Francesca Puca2, Prasenjit Dey3, Gabriel G Malouf7, Xiaoping Su8, Liren Li9, Dolores Lopez-Terrada10, Dinesh Rakheja11, Alexander J Lazar12, George J Netto13, Priya Rao14, Alessandro Sgambato15, Anirban Maitra16, Durga N Tripathi17, Cheryl L Walker17, Jose A Karam18, Timothy P Heffernan1, Andrea Viale2, Charles W M Roberts19, Pavlos Msaouel20, Nizar M Tannir21, Giulio F Draetta22, Giannicola Genovese23.
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.Entities:
Keywords: BIRC5; ER stress; MYC; SMARCB1; autophagy; embryonic mosaic GEM models; p53; proteasome inhibitors; renal medullary carcinoma; rhabdoid tumors
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Year: 2019 PMID： 30753823 PMCID： PMC7876656 DOI： 10.1016/j.ccell.2019.01.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585