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

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

  • Nat Struct Mol Biol. 2011 Nov 27;18(12):1331-1335. doi: 10.1038/nsmb.2189.
Matilde Murga  # 1,  Stefano Campaner  # 2,  Andres J Lopez-Contreras 1,  Luis I Toledo 1,  Rebeca Soria 1,  Maria F Montaña 1,  Luana D' Artista 2,  Thomas Schleker 2,  Carmen Guerra 3,  Elena Garcia 4,  Mariano Barbacid 3,  Manuel Hidalgo 4,  Bruno Amati 2 5,  Oscar Fernandez-Capetillo 1
Affiliations

Affiliations

  • 1 Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 2 Department of Experimental Oncology, European Institute of Oncology (IEO), at the IFOM-IEO Campus, Milan, Italy.
  • 3 Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 4 Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 5 Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), at the IFOM-IEO Campus, Milan, Italy.
  • # Contributed equally.
PMID: 22120667 DOI: 10.1038/nsmb.2189
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.

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