Alterations in the SWI/SNF chromatin remodeling complex have been implicated in human malignancies. Biallelic inactivation of the core subunits SMARCB1 and SMARCA4 are associated with particularly aggressive forms of pediatric cancer known as malignant rhabdoid tumors (MRTs) and atypical theratoid/rhabdoid tumors (AT/RTs). MRTs and AT/RTs are characterized by simple genomes and lack of somatic events, suggesting that dysregulation of SWI/SNF machinery is sufficient to induce a highly malignant state. However, the lack of a conditional genetic model of MRT has precluded the investigation of the molecular bases and dependencies associated with SMARCB1 loss. To this aim, we have developed a novel embryonic mosaic mouse model of MRTs of the liver. Using this mouse model, we performed a systematic functional investigation of vulnerabilities in the context of SMARCB1 loss in order to identify novel treatments for these diseases. Embryonic mosaic models of MRTs of the liver were generated by transuterine delivery of adenoviral vectors carrying the Cre recombinase under a tissue-specific promoter (Adx-Alb-Cre) to target SMARCB1LoxP/LoxP embryos at embryonic day E12-14 in order to study the effect of SMARCB1 ablation on development and tumorigenesis. Such an approach allowed us to target the developing liver epithelial compartment and to bypass the perinatal lethality observed with tissue-specific Cre deleter strains. This approach results in postnatal expansion of the epithelial compartment and in the emergence of rhabdoid tumors in a subset of cases. Upon investigation of the early effects of SMARCB1 ablation during mouse development and tumorigenesis, we found that livers in these embryonic mosaic murine models undergo profound metabolic changes resulting in a dramatic activation of cellular programs involved in the maintenance of proteostasis in response to ER stress and autophagy. To functionally validate the hypothesis that SMARCB1 loss confers sensitivity to proteotoxic agents, embryonic mosaic murine models of MRTs of the liver were treated with combinations of bortezomib and chloroquine, resulting in suppression of tumor growth and prolonged survival. Murine transplantation models of MRT treated with combinations of bortezomib and chloroquine also resulted in a significant increase in survival. Additionally, immunohistochemical studies of pediatric MRTs showed significant accumulation of markers of ER stress, and autophagy in comparison to normal tissue. The use of a novel embryonic mosaic models of MRT demonstrated that SMARCB1 disruption during liver embryogenesis caused activation of anabolic pathways and an increase in UPR, ER stress response, and autophagy. Overall, our preclinical study provides the rationale for a novel therapeutic approach aimed at exploiting a “collateral proteopathy” characteristic of SMARCB1-deficient malignancies and at the repositioning of existing drugs that have already shown acceptable toxicity profiles.

Citation Format: Melinda Soeung, Alessandro Carugo, Frederick Scott Robinson, Rosalba Minelli, Federica Carbone, Anirban Maitra, Andrea Viale, Charles W.M. Roberts, Nizar Tannir, Giulio F. Draetta, Giannicola Genovese. Perturbation of proteostasis is lethal in SMARCB1-deficient tumors [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B40.