Introduction/Background High-grade serous ovarian cancer (HGSOC) is the most lethal form of gynaecological malignancy. Despite usual initial chemosensitivity, the majority of patients develop resistance to platinum chemotherapy and eventually die. Current treatment options for platinum resistant disease remain limited. The role of the PI3K/AKT/mTOR pathway has been well described in chemoresistant disease, in particular through activation of AKT in response to platinum treatment, by the DNA damage response protein DNA-PK. Our laboratory previously demonstrated that inhibition of AKT or DNA-PK re-sensitises clinically-acquired platinum resistant cell lines to cisplatin. Work to date has been carried out in immortalised cell lines, which inherently develop phenotypic/genotypic alterations over time. The present project aims to confirm our previous findings, using primary HGSOC tumour cells and 3D models, and correlate responses to DNA-PK copy number and gene expression data.
Methodology Tumour cell cultures established from HGSOC tumour and ascites samples were treated with cisplatin plus/minus AKT or DNA-PK inhibitors, and their apoptotic response and cell viability were measured. RNA and DNA were extracted from tumour cells, and gene expression and copy-number analysis were performed using qPCR.
Results Following treatment with cisplatin in combination with either AKT or DNA-PK inhibitors, an enhanced apoptotic response was observed in primary cells from ascites (n=4, p<0.01, p<0.05) and tumour (n=4, p<0.05) compared to cisplatin treatment alone. DNA-PK amplification was detected in a number of HGSOC tumour samples and immortalised chemoresistant cell lines. Strong synergy was observed in a panel of platinum resistant HGSOC cell lines when combining AKT or DNA-PK inhibitors with cisplatin.
Conclusion In each primary case of HGSOC examined, AKT or DNA-PK inhibition significantly enhanced the apoptotic response of patient derived tumour cells to cisplatin, demonstrating the efficacy of AKT of DNA-PK as potential therapeutic targets for chemoresistant HGSOC.
Disclosure Professor Christina Fotopoulou, COI: advisory boards and honoraria from Roche, Tesaro, Sequana, Olympus, Astra Zeneca.
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