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Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma, Ohmura S et al., Molecular Cancer 2021

Immunhistochemical analysis for DNA damage (γH2A.X) in Ewing sarcoma xenograft Left, without RRM2 silencing; right RRM2 silencing.
© DKFZ

Ewing sarcoma (EwS) is a highly aggressive bone- or soft tissue-associated cancer in children, adolescents, and young adults, for which the development of more effective therapies remains an unmet medical need. This study not only sheds light on a critical role of RRM2, a small subunit of the ribonucleotide reductase, which catalyzes the rate limiting de novo DNA synthesis, for aggressive phenotypes, but also demonstrated that RRM2 can be a clinically actionable target in EwS.

Employing a multi-layered screening approach, we carefully selected candidate genes, which are highly expressed in EwS but not in normal tissues, whose overexpression potentially confers negative clinical outcome, and for which a selective drug and pharmacokinetic data were available. In this screen, we identified a single putative druggable target, RRM2, that fulfilled these criteria. Using transcriptome and matched datasets of clinical tumor samples, we showed that RRM2 mRNA and protein overexpression is associated with an aggressive phenotype such as early metastasis or disease recurrence and thus poor overall survival of patients, suggesting RRM2 as potential prognostic biomarker for EwS. In agreement with these clinical findings, RRM2 silencing as well as its pharmacological inhibition with the specific inhibitor triapine (3-AP) significantly reduced EwS growth in vitro and in vivo. Interestingly, triapine could overcome chemoresistance against doxorubicin or gemcitabine, and synergize with cell cycle checkpoint inhibitors for CHEK1 or WEE1 in cell models. Collectively, this study provided a translational rationale to exploit RRM2 as a novel therapeutic target in EwS, encouraging further (pre)clinical investigations. (pubmed)

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