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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Nature Structural and Molecular Biology
Vol/bind	18
Udgave nummer	12
Sider (fra-til)	1331-5
Antal sider	5
ISSN	1545-9993
DOI	https://doi.org/10.1038/nsmb.2189
Status	Udgivet - dec. 2011
Udgivet eksternt	Ja

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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, bind 18, nr. 12, s. 1331-5. https://doi.org/10.1038/nsmb.2189

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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.",

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author = "Matilde Murga and Stefano Campaner and Lopez-Contreras, {Andres J} and Toledo, {Luis I} and Rebeca Soria and Monta{\~n}a, {Maria F} and Luana D'Artista and Thomas Schleker and Carmen Guerra and Elena Garcia and Mariano Barbacid and Manuel Hidalgo and Bruno Amati and Oscar Fernandez-Capetillo",

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AU - Schleker, Thomas

AU - Guerra, Carmen

AU - Garcia, Elena

AU - Barbacid, Mariano

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AU - Amati, Bruno

AU - Fernandez-Capetillo, Oscar

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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

KW - Protein Kinase Inhibitors

KW - Protein Kinases

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins c-myc

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

Abstract

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