Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma

• Published in: Cancer cell 2013-12, Vol.24 (6), p.710-724
• Main Authors: Chen, Xiang, Stewart, Elizabeth, Shelat, Anang A., Qu, Chunxu, Bahrami, Armita, Hatley, Mark, Wu, Gang, Bradley, Cori, McEvoy, Justina, Pappo, Alberto, Spunt, Sheri, Valentine, Marcus B., Valentine, Virginia, Krafcik, Fred, Lang, Walter H., Wierdl, Monika, Tsurkan, Lyudmila, Tolleman, Viktor, Federico, Sara M., Morton, Chris, Lu, Charles, Ding, Li, Easton, John, Rusch, Michael, Nagahawatte, Panduka, Wang, Jianmin, Parker, Matthew, Wei, Lei, Hedlund, Erin, Finkelstein, David, Edmonson, Michael, Shurtleff, Sheila, Boggs, Kristy, Mulder, Heather, Yergeau, Donald, Skapek, Steve, Hawkins, Douglas S., Ramirez, Nilsa, Potter, Philip M., Sandoval, John A., Davidoff, Andrew M., Mardis, Elaine R., Wilson, Richard K., Zhang, Jinghui, Downing, James R., Dyer, Michael A.
• Format: Article
• Language: English
• Subjects: Animals; Clonal Evolution; Gene Dosage; Homeostasis; Humans; Loss of Heterozygosity; Mice; Mutation; Oxidative Stress; Rhabdomyosarcoma, Embryonal - drug therapy; Rhabdomyosarcoma, Embryonal - genetics; Rhabdomyosarcoma, Embryonal - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2013.11.002

Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS. •There are higher rates of mutation in ERMS than in ARMS tumors•RAS pathway mutations are associated with intermediate- and high-risk ERMS•ERMS tumor cells have elevated oxidative stress•ERMS tumors are sensitive to drugs that target oxidative stress