On_target_mutations_confer_resistance_to_WRN_helicase_inhibitors_in_Microsatellite_Unstable_Cancer_Cells

Acquired resistance remains a major limitation of targeted therapy in MSI cancers. In this project, we will model therapy-driven evolution by treating MSI cancer cell lines and patient-derived organoids engrafted in vivo with selective targeted agents until resistant populations arise. Resistant tumours will be explanted and subjected to targeted DNA sequencing of ~400 candidate genes implicated in drug response, DNA repair, and tumour evolution. This approach will enable systematic identification of recurrent resistance variants and candidate mechanisms, supporting biomarker development and rational combination strategies to improve durability of response.