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

Alessandro Carugo, Rosalba Minelli, Luigi Sapio, Melinda Soeung, Federica Carbone, Frederick S. Robinson, James Tepper, Ziheng Chen, Sara Lovisa, Maria Svelto, Samirkumar Amin, Sanjana Srinivasan, Edoardo Del Poggetto, Sara Loponte, Francesca Puca, Prasenjit Dey, Gabriel G. Malouf, Xiaoping Su, Liren Li, Dolores Lopez-TerradaDinesh Rakheja, Alexander J. Lazar, George J. Netto, Priya Rao, Alessandro Sgambato, Anirban Maitra, Durga N. Tripathi, Cheryl L. Walker, Jose A. Karam, Timothy P. Heffernan, Andrea Viale, Charles W.M. Roberts, Pavlos Msaouel, Nizar M. Tannir, Giulio F. Draetta, Giannicola Genovese

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)204-220.e9
JournalCancer Cell
Issue number2
StatePublished - Feb 11 2019


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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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