| Autor: |
Tomasini PP; Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre, Avenida Sarmento Leite, 245, Porto Alegre 90050-170, Brazil.; Post-Graduation Program in Cell and Molecular Biology, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, Porto Alegre 91501-970, Brazil., Guecheva TN; Cardiology Institute of Rio Grande do Sul, University Foundation of Cardiology (IC-FUC), Porto Alegre 90620-000, Brazil., Leguisamo NM; Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre, Avenida Sarmento Leite, 245, Porto Alegre 90050-170, Brazil., Péricart S; Laboratoire D'Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irène-Joliot-Curie, 31059 Toulouse, France., Brunac AC; Laboratoire D'Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irène-Joliot-Curie, 31059 Toulouse, France., Hoffmann JS; Laboratoire D'Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irène-Joliot-Curie, 31059 Toulouse, France., Saffi J; Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre, Avenida Sarmento Leite, 245, Porto Alegre 90050-170, Brazil.; Post-Graduation Program in Cell and Molecular Biology, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, Porto Alegre 91501-970, Brazil. |
| Abstrakt: |
Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies. |
