Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. The SWI/SNF complex, specifically, is involved in a plethora of biologic functions including cell cycle regulation, terminal differentiation, and regulation of cell metabolism. The crucial chromatin-remodeling function of the SWI/SNF complex during organogenesis and tissue specification is further supported by clinical data showing that the biallelic inactivation of the core subunits SMARCB1 and SMARCA4 results in the emergence of extremely aggressive pediatric malignancies characterized by a dramatic impairment of cell cycle regulation and cellular differentiation programs, resulting in highly lethal diseases characterized by early onset, widespread metastatic dissemination, and resistance to chemotherapy. So far the lack of conditional genetic models of malignant rhabdoid tumors (MRTs) made difficult to investigate the molecular bases of malignant transformation as well as the existence of dependencies associated with SMARCB1 loss. In order to identify the functional vulnerabilities of SMARCB1-deficient cancers, we developed an embryonic mosaic model of malignant rhabdoid tumors (MRTs) that faithfully recapitulates the clinicopathologic features of human disease. By using this novel experimental system we discovered that, upon SMARCB1 ablation, embryonic epithelial progenitors undergo a profound anabolic reprogramming resulting in a global increase in protein biosynthesis and in the adaptive activation of UPR and ER stress response. As a consequence, murine and human SMARCB1-deficient malignancies display an exquisite sensitivity to agents inducing proteotoxic stress and to the pharmacologic and genetic perturbation of autophagy. Our findings, therefore, have immediate clinical implications, paving the way for drug repositioning trials investigating combinations of agents with already known safety profiles targeting simultaneously UPR and the authopagic catabolic machinery in a class of orphan diseases affecting children with limited therapeutic options.

Note: This abstract was not presented at the conference.

Citation Format: Giannicola Genovese, Alessandro Carugo, Rosalba Minelli, Frederick, Scott Robinson, Pavlos Msaouel, Tim Heffernan, Andrea Viale, Nizar Tannir, Giulio Draetta. Perturbation of proteostasis is lethal in SMARCB1-deficient tumors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A03.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.