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oai:gredos.usal.es:10366/1543572026-06-19T14:47:10Zcom_10366_4028com_10366_3947com_10366_3946com_10366_3823com_10366_4577com_10366_4576col_10366_4029col_10366_4578

00925njm 22002777a 4500 dc Mackintosh Ginel, Carlos Jesús author García Domínguez, Daniel José author Ordóñez García, José Luis author Ginel Picardo, Alicia author Smith, P. G. author Sacristán Martín, María Paz author de Álava Casado, Enrique author 2013-03-14 [EN]Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of children and young adults in which finding effective new targeted therapies is imperative. Here, we report an in-depth preclinical study of the investigational cullin-RING ubiquitin ligase (CRL) inhibitor MLN4924 in ES, as we have recently demonstrated the implication of a CRL component in the ES pathogenesis. First, our results support a high sensitivity of ES cells to MLN4924 growth inhibition both in vitro (14 ES cell lines tested, median IC50¼81 nM) and in tumor xenografts (tumor regression achieved with 60 mg/kg BID, subcutaneously, n¼9). Second, we report a dual mechanism of action of MLN4924 in ES cells: while a wide range of MLN4924 concentrations (B30–300 nM) trigger a G2 arrest that can only be rescued by WEE1 kinase inhibition or depletion, saturating doses of the drug (4300 nM) cause a delay in S-phase progression concomitant with unbalanced CDK2-Cyclin E and CDK2-Cyclin A relative levels (accumulation of the first and depletion of the latter). The aberrant presence of CDC6 in the nucleus at late S-phase cell cycle stage confirmed the loss of CDK2-Cyclin A-specific functions. Remarkably, other mechanisms explored (P27 accumulation and DNA damage signaling pathways) were found unable to explain MLN4924 effects, strengthening the specificity of our findings and suggesting the absence of functionality of some CRL substrates accumulated in response to MLN4924. This study renders a rationale for clinical trials and contributes molecular mechanisms for a better understanding of this promising antitumoral agent. Mackintosh, García-Domínguez, Ordóñez, Ginel-Picardo, Smith, Sacristán, & De Álava. (2013). WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells. Oncogene, 32(11), 1441-1451. https://doi.org/10.1038/ONC.2012.153 http://hdl.handle.net/10366/154357 10.1038/ONC.2012.153 1476-5594 WEE1 Cyclin A Cyclin E P27 MLN4924 Ewing sarcoma WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells