Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors

Matilde Murga, Stefano Campaner, Andres J. Lopez-Contreras, Luis I. Toledo, Rebeca Soria, Maria F. Montaña, Luana D'Artista, Thomas Schleker, Carmen Guerra, Elena Garcia, Mariano Barbacid, Manuel Hidalgo, Bruno Amati, Oscar Fernandez-Capetillo

Research output: Contribution to journalArticlepeer-review

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-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.

Original languageEnglish
Pages (from-to)1331-1335
Number of pages5
JournalNature Structural and Molecular Biology
Volume18
Issue number12
DOIs
Publication statusPublished - Dec 2011

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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