EP964 Targeting AKT and DNA-PK as a therapeutic strategy in platinum resistant high-grade serous ovarian cancer

Introduction/Background High-grade serous ovarian cancer (HGSOC) is the most lethal form of gynaecological malignancy. Despite initial sensitivity to platinum chemotherapy, the majority of patients develop resistance to treatment and eventually die. Current treatment options for platinum-resistant patients are limited. The role of the PI3K/AKT/mTOR pathway has been described in chemo-resistant HGSOC, in particular through activation of AKT by DNA-PK in response to platinum treatment. As increasing numbers of AKT and DNA-PK inhibitors advance to clinical trials, determining mechanism of action and efficacy is crucial. This project aims to evaluate inhibition of AKT or DNA-PK as a therapeutic strategy to target platinum resistance in HGSOC, and identify proteomic signatures confirming mechanism of action and target inhibition. Methodology A panel of seven AKT and DNA-PK inhibitors were tested in combination with cisplatin chemotherapy in immortalised HGSOC cell lines and primary tumour cells cultured from HGSOC tumour/ascites samples. Clonogenic assays were performed to establish effect of inhibitor treatment in combination with cisplatin chemotherapy on the ability of cells to form colonies. Isobologram assays were performed to establish synergy/antagonism between inhibitors and cisplatin chemotherapy. Proteomic Reverse Phase Protein Array (RPPA) was performed to determine the mechanism of action of inhibitors, and results were confirmed with immunoblotting. Results Treatment with AKT or DNA-PK inhibitors in combination with cisplatin led to significantly enhanced apoptotic responses in immortalised platinum-resistant HGSOC cell lines (n=5), and in primary cells derived from ascites or tumour (n=4, p Conclusion In platinum-resistant HGSOC cells, AKT or DNA-PK inhibition functioned synergistically with cisplatin and reduced cell growth and proliferation. In both immortalised and primary HGSOC cell lines tested, AKT or DNA-PK inhibition significantly enhanced the apoptotic response to cisplatin demonstrating the efficacy of AKT or DNA-PK as potential therapeutic targets in chemoresistant HGSOC. By improving patient response to treatment, AKT and DNA-PK inhibitors could expand the therapeutic options for patients with platinum-resistant HGSOC, improving overall survival. Disclosures CF: advisory boards and honoraria from Roche, Tesaro, Sequana, Olympus, Astra Zeneca. Other authors have no conflict of interest.