Exposure to chemotherapy alters secondary drug sensitivity without genomic alterations in patient-derived ovarian cancer organoid models

Ovarian cancer has significant morbidity and mortality due to high rates of resistance to chemotherapy and recurrence. Our objective was to deploy patient-derived organoid (PDO) models of ovarian cancer to assess secondary drug sensitivity after exposure to chemotherapy in vitro. Tumor specimens were collected from patients who received platinum-based chemotherapy, and PDO models were generated from four primary ovarian patient tumors as well as paired metastatic lesions and tumor cells in ascites fluid for one of the four cases. Comparison of tumor samples to the corresponding PDO model revealed a > 90% overlap in single nucleotide variants (SNVs), establishing model validity. PDOs were exposed to a three-day pulse of chemotherapy (carboplatin + paclitaxel), followed by assessment of sensitivity to a panel of therapeutic agents used in the adjuvant/recurrent setting. Chemo-exposed PDOs exhibited higher relative viability to combination of carboplatin and paclitaxel than matched chemo-naïve PDOs. Genomic analysis comparing treatment-naïve to chemo-exposed PDOs revealed genomic stability. In drug sensitivity studies with agents used in the adjuvant and recurrent settings, chemo-exposed PDOs showed greater sensitivity to the angiokinase inhibitor cediranib, and increased resistance to topotecan. These data substantiate that PDO models retain primary tumor properties and intertumoral heterogeneity, and short-term culture is sufficient to reveal differences in drug sensitivity.