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

doi:10.1038/nsmb.2189

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

245 Citations (Scopus)

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 language	English
Journal	Nature Structural and Molecular Biology
Volume	18
Issue number	12
Pages (from-to)	1331-5
Number of pages	5
ISSN	1545-9993
DOIs	https://doi.org/10.1038/nsmb.2189
Publication status	Published - Dec 2011
Externally published	Yes

Keywords

Adenocarcinoma
Animals
Antineoplastic Agents
Apoptosis
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins
DNA Damage
Lymphoma
Mice
Pancreatic Neoplasms
Protein Kinase Inhibitors
Protein Kinases
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins c-myc
Stress, Physiological

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nsmb.2189

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Murga, M., Campaner, S., Lopez-Contreras, A. J., Toledo, L. I., Soria, R., Montaña, M. F., D'Artista, L., Schleker, T., Guerra, C., Garcia, E., Barbacid, M., Hidalgo, M., Amati, B., & Fernandez-Capetillo, O. (2011). Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nature Structural and Molecular Biology, 18(12), 1331-5. https://doi.org/10.1038/nsmb.2189

Murga, M, Campaner, S, Lopez-Contreras, AJ, Toledo, LI, Soria, R, Montaña, MF, D'Artista, L, Schleker, T, Guerra, C, Garcia, E, Barbacid, M, Hidalgo, M, Amati, B & Fernandez-Capetillo, O 2011, 'Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors', Nature Structural and Molecular Biology, vol. 18, no. 12, pp. 1331-5. https://doi.org/10.1038/nsmb.2189

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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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AB - 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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KW - Ataxia Telangiectasia Mutated Proteins

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KW - DNA Damage

KW - Lymphoma

KW - Mice

KW - Pancreatic Neoplasms

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KW - Protein Kinases

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins c-myc

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JO - Nature Structural and Molecular Biology

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ER -

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

Abstract

Keywords

UN SDGs

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