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 - Funding Information:
P.M. was supported by a Conquer Cancer Foundation Young Investigator Award and by a Kidney Cancer Association Young Investigator Award. G.D. was supported by the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Grant and the Pancreatic Cancer Action Network Translational Research Grant. A.C. was supported by the FIRC-AIRC fellowship. F.C. was supported by the AIRC fellowship. N.M.T. was supported by the Ransom Horne Jr. Professorship for Cancer Research. G.G. was supported by the Barbara Massie Memorial Fund and the CPRIT Research Grant RP170722.
Funding Information:
P.M. was supported by a Conquer Cancer Foundation Young Investigator Award and by a Kidney Cancer Association Young Investigator Award. G.D. was supported by the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Grant and the Pancreatic Cancer Action Network Translational Research Grant. A.C. was supported by the FIRC -AIRC fellowship. F.C. was supported by the AIRC fellowship. N.M.T. was supported by the Ransom Horne Jr. Professorship for Cancer Research. G.G. was supported by the Barbara Massie Memorial Fund and the CPRIT Research Grant RP170722 .
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 -