Mécanismes moléculaires et déterminants de la réponse aux inhibiteurs de topo-isomérases I

Nuclear topoisomerase I (Top1) is involved in the relaxation of DNA supercoiling and plays a pivotal role in the coordination of essential DNA processes such as transcription, replication, DNA recombination and DNA damage signalling. For all these reasons, Top1 has been an attractive target for the development of anticancer drugs, which poison Top1 by trapping the enzyme on its DNA cleavage sites, which results in irreversible DNA lesions that are responsible for their cytotoxicity. They derive from the natural compound camptothecin and two derivatives are approved in the clinic, topotecan and irinotecan; other compounds such as indolocarbazoles and indenoisoquinolines are in development. However, the efficacy of these drugs is often limited by the problem of resistance, which involves various mechanisms at different steps of drug action, from drug transport and/or metabolism to the signalling and/or repair of the DNA lesions that are generated. A better understanding of these mechanisms is a major concern for the future development of new Top1 inhibitors and the identification of biomarkers that could be used to predict tumour response to these drugs in the clinic and to adapt the treatment to each patient.