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oai:repisalud.isciii.es:20.500.12105/179512024-11-29T21:57:48Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Murga, Matilde author Campaner, Stefano author Lopez-Contreras, Andres J author Toledo, Luis I author Soria, Rebeca author Montaña, Maria F author Artista, Luana D' author Schleker, Thomas author Guerra, Carmen author Garcia, Elena author Barbacid, Mariano author Hidalgo, Manuel author Amati, Bruno author Fernandez-Capetillo, Oscar author 2011-11-27 Oncogene-induced replicative stress activates an Atr- and Chk1-dependent response, which has been proposed to be widespread in tumors. We explored whether the presence of replicative stress could be exploited for the selective elimination of cancer cells. To this end, we evaluated the impact of targeting the replicative stress-response on cancer development. In mice (Mus musculus), the reduced levels of Atr found on a mouse model of the Atr-Seckel syndrome completely prevented the development of Myc-induced lymphomas or pancreatic tumors, both of which showed abundant levels of replicative stress. Moreover, Chk1 inhibitors were highly effective in killing Myc-driven lymphomas. By contrast, pancreatic adenocarcinomas initiated by K-Ras(G12V) showed no detectable evidence of replicative stress and were nonresponsive to this therapy. Besides its impact on cancer, Myc overexpression aggravated the phenotypes of Atr-Seckel mice, revealing that oncogenes can modulate the severity of replicative stress-associated diseases. Nat Struct Mol Biol . 2011 ;18(12):1331-1335. 10.1038/nsmb.2189 1545-9985 Nature structural & molecular biology 22120667 http://hdl.handle.net/20.500.12105/17951 Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors.