Molecular basis of chemosensitivity of platinum pre-treated ovarian cancer to chemotherapy

Abstract

Background: Ovarian cancer shows considerable heterogeneity in its sensitivity to chemotherapy both clinically and in vitro. This study tested the hypothesis that the molecular basis of this difference lies within the known resistance mechanisms inherent to these patients' tumours.

Methods: The chemosensitivity of a series of 31 ovarian tumours, all previously treated with platinum-based chemotherapy, was assessed using the ATP-based tumour chemosensitivity assay (ATP-TCA) and correlated with resistance gene expression measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) in a TaqMan Array following extraction of mRNA from formalin-fixed paraffin-embedded tissue. The results were standardised against a housekeeping gene (PBGD), and assessed by multiple linear regression.

Results: Predictive multiple linear regression models were derived for four single agents (cisplatin, gemcitabine, topotecan, and treosulfan), and for the combinations of cisplatin+gemcitabine and treosulfan+gemcitabine. Particularly strong correlations were obtained for cisplatin, gemcitabine, topotecan, and treosulfan+gemcitabine. No individual gene expression showed direct correlation with activity in the ATP-TCA. Genes involved in DNA repair and apoptosis were strongly represented, with some drug pumps also involved.

Conclusion: The chemosensitivity of ovarian cancer to drugs is related to the expression of genes involved in sensitivity and resistance mechanisms.

Figure 1

Box and whisker plot showing the sensitivity of tumours to each drug tested. Index_SUM is higher in resistance, lower in sensitive tumours.

Figure 2

Multiple linear regression analysis by unsupervised forward selection for (A) cisplatin − Adj R²=0.836, P<0.001; (B) doxorubicin − Adj R²=0.524, P<0.007; (C) gemcitabine − Adj R²=0.524, P<0.001; (D) paclitaxel − Adj R²=0.646, P<0.001; (E) topotecan − Adj R²=0.751, P<0.001; (F) treosulfan − Adj R²=0.977, P<0.001; (G) cisplatin+gemcitabine − Adj R²=0.743, P<0.001; (H) treosulfan+gemcitabine − Adj R²=0.753, P<0.001.