Project : Molecular characterization of the checkpoint-dependent replication inhibition in response to camptothecin-induced DNA damage

Chemotherapy is still the standard treatment for a wide range of cancers despite the frequent emergence of chemotherapy resistance. The combination of the ATR checkpoint kinase inhibitor with the chemotherapeutic agent camptothecin stands as a promising strategy to prevent cancer cells from acquiring resistance. This combined treatment inhibits both the initiation and the elongation of DNA replication, yet the molecular mechanism involved remains unknown. This proposal aims at understanding the molecular basis underlying this treatment. Additionally, it aims at anticipating new resistance mechanisms by proposing an unbiased search for suppressor mutations that will indicate how cancer cells can escape cell death. To perform a deep and rapid characterization of the DNA damage response triggered by CPT treatment of synchronously-replicating cells, we will use to yeast Saccharomyces cerevisiae model before translating the results to human cell models in a near future.

We believe that the benefits of this research project will help improving CPT treatments as a sole chemotherapeutic agent and in combination with checkpoint inhibitors. It will also open new research directions thanks to the identification of candidates required for CPT resistance. Finally, it will also bring new insights about the fundamental process of DNA replication, whose deregulation is a hallmark of most cancers.