Abstract PL03-02: Exploiting DNA replication stress for cancer therapies

Abstract

Abstract A feature of most cancers is genomic instability. We and others have proposed a model to explain the presence of such genomic instability. Briefly, we proposed that oncogenes, which are activated in practically all cancers and drive cell proliferation, induce DNA replication stress. The presence of DNA replication stress leads to the formation of DNA double-strand breaks, which, when incorrectly repaired, lead to genomic instability. DNA replication stress is a somewhat non-specific term used to indicate that cells have difficulties to replicate their DNA. Inhibitors of DNA polymerases slow down DNA replication and induce DNA replication stress. However, in this case, the replisome, i.e. the proteins that replicate the DNA, remains intact and DNA double-strand breaks are not formed. Oncogenes induce a different type of DNA replication stress, as select replisomes are disrupted, leaving the DNA “naked” and susceptible to DNA double-strand break formation. Recent results from a number of laboratories have provided great insights on how oncogenes induce DNA replication stress. Specifically, it has been found that oncogenes induce the firing of novel DNA replication origins. These oncogene-induced origins are present within transcribed genes. When these origins fire and DNA replication begins, the replisomes collide with the transcription machinery. These aberrant collisions lead to disruption of the replisome. Disrupted, aka as collapsed, replisomes need to be repaired for DNA replication to restart. Errors in this repair lead to DNA double-strand breaks and genomic instability. The main pathway for repair of collapsed DNA replication forks appears to be break-induced replication. This pathway is used very infrequently by normal cells and, as such, certain proteins that function in this pathway are not essential for normal development. However, their inactivation suppresses cancer development, because cancer cells rely on break-induced replication to repair their collapsed DNA replication forks. It follows that proteins that function in break-induced replication may be good targets for the development of effective, non-toxic cancer therapies. Citation Format: Thanos Halazonetis. Exploiting DNA replication stress for cancer therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL03-02. doi:10.1158/1535-7163.TARG-19-PL03-02