In vivo gene expression changes in EW5 Ewing sarcoma xenografts after IGF-1R or mTOR blockade

Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent IGF-1R or mTOR inhibition might suggest a number of therapeutic combinations that could improve their clinical activity.

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Lamhamedi-Cherradi SE, Menegaz BA, Ramamoorthy V, Vishwamitra D, Wang Y, Maywald RL, Buford AS, Fokt I, Skora S, Wang J, Naing A, Lazar AJ, Rohren EM, Daw NC, Subbiah V, Benjamin RS, Ratan R, Priebe W, Mikos AG, Amin HM, Ludwig JA