Organoid platinum-resistance model identifies KRT17 as a biomarker of targeted therapy in ovarian cancer.

Variable responses to platinum chemotherapy and the emergence of resistant disease drive high mortality in high-grade serous ovarian cancer (HGSOC). To study resistance mechanisms, we developed the organoid drug resistance assay (ODR-test) with patient-derived organoids from our ovarian cancer biobank and identified sustained phenotypic reprogramming and cellular plasticity of organoids under carboplatin pressure as a conserved mechanism irrespective of the basal resistance level. Transcriptional and proteomic analyses revealed changes in cell adhesion and differentiation as adaptive responses that lead to an increase in resistance. We identified Keratin 17 (KRT17) as a mediator of platinum resistance and validated its function by CRISPR-Cas9 and overexpression. Additionally, we found that KRT17 expression status (K-score) is a significant negative prognostic histopathological biomarker in a large cohort (N = 384) of patients with advanced HGSOC. In organoids, increased KRT17 levels enhanced sensitivity to PI3K/Akt inhibitors alpelisib and afuresertib, highlighting the potential of KRT17 as a stratification biomarker for targeted therapies.