title: Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors.
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.
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Matilde
authors: M
authors: Murga
authors: Department of Experimental Oncology, European Institute of Oncology (IEO), at the IFOM-IEO Campus, Milan, Italy.
authors: Stefano
authors: S
authors: Campaner
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Andres J
authors: AJ
authors: Lopez-Contreras
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Luis I
authors: LI
authors: Toledo
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Rebeca
authors: R
authors: Soria
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Maria F
authors: MF
authors: Montaña
authors: Department of Experimental Oncology, European Institute of Oncology (IEO), at the IFOM-IEO Campus, Milan, Italy.
authors: Luana D'
authors: L
authors: Artista
authors: Department of Experimental Oncology, European Institute of Oncology (IEO), at the IFOM-IEO Campus, Milan, Italy.
authors: Thomas
authors: T
authors: Schleker
authors: Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Carmen
authors: C
authors: Guerra
authors: Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Elena
authors: E
authors: Garcia
authors: Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Mariano
authors: M
authors: Barbacid
authors: Clinical Research Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Manuel
authors: M
authors: Hidalgo
authors: Department of Experimental Oncology, European Institute of Oncology (IEO), at the IFOM-IEO Campus, Milan, Italy.|Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), at the IFOM-IEO Campus, Milan, Italy.
authors: Bruno
authors: B
authors: Amati
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Oscar
authors: O
authors: Fernandez-Capetillo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011494:Protein Kinases; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D017346:Protein Serine-Threonine Kinases