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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Specific mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2A, a hereditary syndrome characterized by tumorigenesis in multiple glandular elements. In rare instances, MEN2A-associated germline RET mutations have also occurred with non-MEN2A associated cancers. One such germline mutant RET mutation occurred concomitantly in a young adult diagnosed with alveolar rhabdomyosarcoma, a pediatric and young adult soft-tissue cancer with a generally poor prognosis. Although tumor tissue samples were initially unable to provide a viable cell culture for study, tumor tissues were sequenced for molecular characteristics. Through a hierarchical clustering approach, the index case sample was matched to several genetically similar cell models, which were transformed to express the same mutant RET as the index case and used to explore potential therapeutic options for mutant RET -bearing alveolar rhabdomyosarcoma. We also determined whether the RET mutation associated with the index case caused synthetic lethality to select clinical agents. From our investigation, we did not identify synthetic lethality associated with the expression of that patient's RET variant, and overall we did not find experimental evidence for the role of RET in rhabdomyosarcoma progression., (© 2021 Berlow et al.; Published by Cold Spring Harbor Laboratory Press.)

In this case report we evaluate the genetics of and scientific basis of therapeutic options for a 14-yr-old male patient diagnosed with metastatic PAX3-FOXO1 fusion positive alveolar rhabdomyosarcoma. A distinguishing genetic feature of this patient was a germline RET C634F mutation, which is a known driver of multiple endocrine neoplasia type 2A (MEN2A) cancer. Through sequential DNA and RNA sequencing analyses over the patient's clinical course, a set of gene mutations, amplifications, and overexpressed genes were identified and biological hypotheses generated to explore the biology of RET and coexisting signaling pathways in rhabdomyosarcoma. Somatic genetic abnormalities identified include CDK4 amplification and FGFR4 G388R polymorphism. Because of the initial lack of patient-derived primary cell cultures, these hypotheses were evaluated using several approaches including western blot analysis and pharmacological evaluation with molecularly similar alveolar rhabdomyosarcoma cell lines. Once a primary cell culture became available, the RET inhibitor cabozantinib was tested but showed no appreciable efficacy in vitro, affirming with the western blot negative for RET protein expression that RET germline mutation could be only incidental. In parallel, the patient was treated with cabozantinib without definitive clinical benefit. Parallel chemical screens identified PI3K and HSP90 as potential tumor-specific biological features. Inhibitors of PI3K and HSP90 were further validated in drug combination synergy experiments and shown to be synergistic in the patient-derived culture. We also evaluated the use of JAK/STAT pathway inhibitors in the context of rhabdomyosarcomas bearing the FGFR4 G388R coding variant. Although the patient succumbed to his disease, study of the patient's tumor has generated insights into the biology of RET and other targets in rhabdomyosarcoma., (© 2020 Crawford et al.; Published by Cold Spring Harbor Laboratory Press.)