58 In vitro chemosensitivity of patient-derived ovarian cancer samples is not correlated with homologous recombination deficiency, platinum sensitivity, or cancer stem cell frequency

Homologous recombination deficiency (HRD) is a biomarker of response to poly-ADP ribose inhibitor (PARPi) treatment in epithelial ovarian cancer (EOC). Clinical studies have demonstrated high correlation between platinum sensitivity and response to PARPi. Chemoresistance and cancer recurrence are driven, in part, by the population of cancer stem-like cells (CSCs) that persist despite primary treatment. We hypothesized that in vitro response to cisplatin and olaparib are correlated with one another and with HRD status, clinical platinum response, and CSC frequency. Published cisplatin IC50 for EOC is between 3 and 14 µM, and olaparib IC50 is 0.3 nM–21 µM. Chemosensitivity was characterized via MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay. CSC frequency was determined via flow cytometry. Experiments were performed in triplicate. Clinical information on genetic status and platinum sensitivity were extracted from the electronic medical records. We identified 15 cell types for study, 12 derived from patient (PD) samples collected via institutional biobank and 3 immortalized cell lines commonly studied in ovarian cancer. 10/15 PD cell types were derived from patients with platinum sensitive EOC; of the remaining 5, 3 were platinum resistant, one platinum refractory, and one is currently undergoing primary adjuvant chemotherapy. 5 cell types are proficient in homologous recombination (HRP), while 9 are HRD. Cisplatin IC50s for HRP cell types were 3.65–28.77 µM and 0.93–27.28 µM for HRD cells (table). Olaparib IC50s were 5.11–10.37 µM (HRP) and 3.77–15.41 µM (HRD) (Table 1). Frequency of CSCs ranged from 0.165 to 6.69% (Table 1). a sample of 15 patient-derived cell types, chemosensitivity to cisplatin and olaparib varied significantly. In contrast to clinical studies, HRD status did not reliably predict in vitro chemosensitivity to either cisplatin or olaparib. Furthermore, chemosensitivity to cisplatin and olaparib were not consistently correlated with one another. This suggests that platinum response may not be an adequate surrogate to predict PARPi response. CSC population did not correlate with chemosensitivity in 3 cell types. Characterization of CSC populations in the remaining cell types is ongoing. Download : Download high-res image (228KB)Download : Download full-size image