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

Se ha descrito un método que permite destruir de modo selectivo las células tumorales, siempre y cuando estas presenten cierta propiedad: el estrés replicativo, una replicación deficiente del ADN. Esta característica hace posible diferenciar los tumores del tejido sano, una de las dificultades principales a la hora de tratar el cáncer. Basándose en el hecho de que algunos tumores exhiben tasas muy altas de estrés replicativo, un equipo ha demostrado que estos responderán a un tratamiento con fármacos que inhiban los mecanismos que poseen las células para hacer frente a este tipo de estrés. 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-RasG12Vshowed 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.

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. « Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors ». Nat Struct Mol Biol [En ligne]. 27 Noviembre 2011,. Vol. advance online publication,. Disponible sur : < http://dx.doi.org/10.1038/nsmb.2189 >