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Targeting AKT and DNA-PK in Platinum-Resistant High-Grade Serous Ovarian Cancer

Conference Correspondent

The phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin pathway is associated with chemotherapy-resistant high-grade serous ovarian cancer.1 Platinum-based chemotherapy can lead to activation of AKT, leading to resistance.2 A number of inhibitors of AKT and DNA-PK are under study. Researchers sought to evaluate the inhibition of AKT or DNA-PK as a strategy to target platinum resistance in high-grade serous ovarian cancer and to confirm the mechanism of action.

A panel of 7 AKT and DNA-PK inhibitors were evaluated in combination with cisplatin chemotherapy. These were tested in immortalized high-grade serous ovarian cancer cell lines and primary tumor cells cultured from high-grade serous ovarian cancer tumor and ascites samples. In both immortalized platinum-resistant high-grade serous ovarian cancer cell lines and in primary cells derived from ascites or tumor, treatment with AKT or DNA-PK inhibitors in combination with cisplatin led to significantly enhanced apoptotic response when compared with cisplatin treatment alone. Compared with cisplatin treatment alone, fewer cell colonies were observed with increasing concentrations of AKT or DNA-PK inhibitors in combination with cisplatin in the platinum-resistant high-grade serious ovarian cancer cell lines.

When the panel of inhibitors were combined with cisplatin, varying synergistic effects were observed. The AKT inhibitor uprosertib displayed strong synergy with cisplatin. Its mechanism of action in targeting the PI3K/AKT pathway was demonstrated.

In platinum-resistant high-grade serous ovarian cancer cells, AKT or DNA-PK inhibitors functioned synergistically with cisplatin. This resulted in reduced cell growth and proliferation. In both the immortalized and primary high-grade serous ovarian cancer cell lines tested, AKT or DNA-PK inhibition significantly enhanced the apoptotic response to cisplatin. Researchers conclude that this demonstrates the efficacy of AKT or DNA-PK as potential therapeutic targets in chemoresistant high-grade serous ovarian cancer. The use of AKT and DNA-PK inhibitors may improve patient response to treatment and, in turn, may improve overall survival for patients with platinum-resistant high-grade serous ovarian cancer.

Abstract 290. ESGO 2020.


References

  1. Ghoneum A, Said N. PI3K-AKT-mTOR and NFκB pathways in ovarian cancer: implications for targeted therapeutics. Cancers (Basel). 2019;11(7):949.
  2. Avan A, Narayan R, Giovannetti E, Peters GJ. Role of AKT signaling in resistance to DNA-targeted therapy. World J Clin Oncol. 2016;7(5):352-369.

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