TY - JOUR
T1 - p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors
AU - Carugo, Alessandro
AU - Minelli, Rosalba
AU - Sapio, Luigi
AU - Soeung, Melinda
AU - Carbone, Federica
AU - Robinson, Frederick S.
AU - Tepper, James
AU - Chen, Ziheng
AU - Lovisa, Sara
AU - Svelto, Maria
AU - Amin, Samirkumar
AU - Srinivasan, Sanjana
AU - Del Poggetto, Edoardo
AU - Loponte, Sara
AU - Puca, Francesca
AU - Dey, Prasenjit
AU - Malouf, Gabriel G.
AU - Su, Xiaoping
AU - Li, Liren
AU - Lopez-Terrada, Dolores
AU - Rakheja, Dinesh
AU - Lazar, Alexander J.
AU - Netto, George J.
AU - Rao, Priya
AU - Sgambato, Alessandro
AU - Maitra, Anirban
AU - Tripathi, Durga N.
AU - Walker, Cheryl L.
AU - Karam, Jose A.
AU - Heffernan, Timothy P.
AU - Viale, Andrea
AU - Roberts, Charles W.M.
AU - Msaouel, Pavlos
AU - Tannir, Nizar M.
AU - Draetta, Giulio F.
AU - Genovese, Giannicola
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/2/11
Y1 - 2019/2/11
N2 - 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.
AB - 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.
KW - BIRC5
KW - ER stress
KW - MYC
KW - SMARCB1
KW - autophagy
KW - embryonic mosaic GEM models
KW - p53
KW - proteasome inhibitors
KW - renal medullary carcinoma
KW - rhabdoid tumors
UR - http://www.scopus.com/inward/record.url?scp=85060850069&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060850069&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2019.01.006
DO - 10.1016/j.ccell.2019.01.006
M3 - Article
C2 - 30753823
AN - SCOPUS:85060850069
SN - 1535-6108
VL - 35
SP - 204-220.e9
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -