Targeting oncogene-induced replication stress for cancer therapy

 

Seminar

Targeting oncogene-induced replication stress for cancer therapy

Óscar Fernández-Capetillo, PhD

Targeting oncogene-induced replication stress for cancer therapy Dr. Óscar Fernández-Capetillo laboratory has focused much of its research in trying to understand how cells respond to "replicative stress" (RS), a type of DNA damage which arises unavoidably every time that a cell replicates its DNA, and which is mainly prevented by a RS-Response (RSR) coordinated by ATR and Chk1 kinases. Given that certain oncogenes can generate substantial amounts of RS, we hypothesized that cells carrying these oncogenes might be "addicted" to a proficient RSR. To explore these ideas, they have generated several cellular, animal and chemical tools for the study of ATR function in mammals. These incluce (1) a cell system in which ATR can be selectively activated at will1; (2) mice with a reduced2 or increased3 RSR, and (3) chemical inhibitors of ATR4. Their early works suggested that ATR inhibitors would indeed be particularly deleterious for tumors with high levels of RS, such as Myc-induced lymphomas5. Their ideas and new results in this area will be presented. 1. Toledo, L. I., Murga, M., Gutierrez-Martinez, P., Soria, R. & Fernandez-Capetillo, O. ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev. 22, 297-302 (2008). 2. Murga, M. et al. A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nature Genetics 41, 891-898 (2009). 3. Lopez-Contreras, A. J., Gutierrez-Martinez, P., Specks, J., Rodrigo-Perez, S. & Fernández-Capetillo, O. An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation. Journal of Experimental Medicine (2012).doi:10.1084/jem.20112147 4. Toledo, L. I. et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat. Struct. Mol. Biol. 18, 721-727 (2011). 5. Murga, M. et al. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat. Struct. Mol. Biol. 18, 1331-1335 (2011).