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- Title
Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors.
- Authors
Murga, Matilde; Campaner, Stefano; Lopez-Contreras, Andres J; Toledo, Luis I; Soria, Rebeca; Montaña, Maria F; D'Artista, Luana; Schleker, Thomas; Guerra, Carmen; Garcia, Elena; Barbacid, Mariano; Hidalgo, Manuel; Amati, Bruno; Fernandez-Capetillo, Oscar
- Abstract
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-RasG12V 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.
- Subjects
MOLECULAR biology; CANCER genetics; LYMPHOPROLIFERATIVE disorders; TUMOR suppressor genes; ONCOGENIC viruses; CANCER cells
- Publication
Nature Structural & Molecular Biology, 2011, Vol 18, Issue 12, p1331
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.2189