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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), 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288422 | GEO | 2025/11/04

REPOSITORIES: GEO

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Project description:Background: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line A2780CBNDXL), along with single agent resistant lines (docetaxel resistant A2780DXL and carboplatin resistant A2780CBN), to investigate the mechanisms which underlie the development of dual drug resistance. Methods: The A2780 epithelial ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis compared to parental co-culture control A2780CC. Changes in selected genes were validated by QPCR and immunoblotting. Results: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. Conclusions: Novel changes in gene expression can occur in the development of dual drug resistance, indicating that dual drug resistance is not a simple combination of the changes occurring in single agent resistance Carboplatin, docetaxel (GSE26129) and carboplatin/docetaxel dual resistant cell lines of ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for each cell line. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments

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

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