Fiche publication
Date publication
février 2019
Journal
Cancer cell
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MALOUF Gabriel
Tous les auteurs :
Carugo A, Minelli R, Sapio L, Soeung M, Carbone F, Robinson FS, Tepper J, Chen Z, Lovisa S, Svelto M, Amin S, Srinivasan S, Del Poggetto E, Loponte S, Puca F, Dey P, Malouf GG, Su X, Li L, Lopez-Terrada D, Rakheja D, Lazar AJ, Netto GJ, Rao P, Sgambato A, Maitra A, Tripathi DN, Walker CL, Karam JA, Heffernan TP, Viale A, Roberts CWM, Msaouel P, Tannir NM, Draetta GF, Genovese G
Lien Pubmed
Résumé
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-p19-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.
Mots clés
BIRC5, ER stress, MYC, SMARCB1, autophagy, embryonic mosaic GEM models, p53, proteasome inhibitors, renal medullary carcinoma, rhabdoid tumors
Référence
Cancer Cell. 2019 Feb 11;35(2):204-220.e9
