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 ARF -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.
Carugo, A., Minelli, R., Sapio, L., Soeung, M., Carbone, F., Robinson, F. S., Tepper, J., Chen, Z., Lovisa, S., Svelto, M., Amin, S., Srinivasan, S., Del Poggetto, E., Loponte, S., Puca, F., Dey, P., Malouf, G. G., Su, X., Li, L., Lopez-Terrada, D., Rakheja, D., Lazar, A. J., Netto, G. J., Rao, P., Sgambato, A., Maitra, A., Tripathi, D. N., Walker, C. L., Karam, J. A., Heffernan, T. P., Viale, A., Roberts, C. W. M., Msaouel, P., Tannir, N. M., Draetta, G. F., Genovese, G., p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors, <<CANCER CELL>>, 2019; 35 (2): 204-220.e9. [doi:10.1016/j.ccell.2019.01.006] [http://hdl.handle.net/10807/170584]
p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors
Sgambato, A.;Genovese, G.
2019
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-p19 ARF -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.
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