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

Variable responses to platinum chemotherapy and the development of resistant disease drive high mortality in high-grade serous ovarian cancer (HGSOC), the deadliest gynecological malignancy. Here, we developed the organoid drug resistance assay (ODR-test) to quantify the patient-specific efficacy of platinum treatment and generated post-platinum lines (ptGPC) as an in vitro model of platinum-resistant ovarian cancer (PROC). We observed a gradual increase in resistance of ptGPC lines, mirroring the clinical outcomes of patients. We have performed RNA-seq analysis from two different donor organoid lines, before carboplatin exposure and paired ptGPC lines of long-term expandable organoids that successfully overcame in vitro drug treatment. By differential expression analysis, we have identified target genes that mediate the cellular response to platinum and play a role in the development of resistant phenotype in ovarian cancer. We have found that carboplatin treatment triggers sustained reprogramming and ptGPC organoids from different donors show common changes in cell adhesion and cytoskeletal organization, indicating the existence of conserved mechanisms that lead to an increase in resistance.