Rise in KRT17 sensitizes platinum-resistant ovarian cancer organoids to targeted therapies

ABSTRACT: Variable responses to platinum chemotherapy and the development of resistant disease drive high mortality in high-grade serous ovarian cancer (HGSOC). Here, we developed the organoid drug resistance assay (ODR-test) to quantify the patient-specific efficacy of platinum treatment and generated post-platinum lines as an in vitro model of platinum-resistant ovarian cancer (PROC). We observed a gradual increase in resistance, mirroring the clinical outcomes of patients. Transcriptional and proteomic analyses of post-platinum phenotypes revealed changes in cell adhesion and differentiation as adaptive mechanisms irrespective of the basal resistance level. We found that Keratin 17 (KRT17) is a mediator of developing resistance and validated its function by CRISPR/Cas9 and overexpression. Additionally, we determined KRT17 (K-score) as a significant negative prognostic factor for survival based on analysis of a tumor microarray (N=377) 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. These findings quantify patient-specific platinum response, identify PROC via KRT17 as a biomarker, and propose alternative targeted therapy for this challenging group of patients.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Ilaria Piga  

LAB HEAD: Jesper Velgaard

PROVIDER: PXD060376 | Pride | 2025-12-22

REPOSITORIES: Pride