Abstract PR04: DNA-PK inhibition resensitizes ovarian cancer cells to cisplatin in vivo and is associated with modulation of AKT pathway signaling

Abstract

Abstract Sustained proliferative signaling and resisting cell death are two fundamental hallmarks of cancer. The AKT pathway is a frequently aberrant, highly interconnected, intracellular signaling network that connects a wide variety of cell stimuli to proliferative and apoptotic cellular control. We have shown that inappropriate control of the AKT pathway underlies failure of chemotherapy in ovarian cancer and furthermore have shown that DNA-PKcs, a component of the non-homologous-end-joining DNA repair pathway, phosphorylates AKT on serine residue 473 in the nucleus of platinum resistant ovarian tumor cells, but not sensitive cells from the same patient. DNA-PK mediated AKT activation in chemoresistant cells results in inhibitory phosphorylation of the pro-apoptotic protein BAD and stabilization of the anti-apoptotic Bcl-2 protein. We report that inhibition of DNA-PK restores response to cisplatin in chemoresistant ovarian cancer cells in vivo. SKOV3 tumor xenografts were implanted subcutaneously into the flanks of Balb/c nu/nu mice and treated with 7.5mg/kg or 10mg/kg DNA-PKcs inhibitor, NU7441 daily (5days on/2 days off) for 2 weeks alone or in combination with 1mg/kg cisplatin twice weekly. DNA-PK inhibition or cisplatin alone were ineffective however in combination decreased tumor growth at 14 days by 89% (7.5mg/kg NU7441) and 90% (10mg/kg NU7441), relative to platinum only treatment. Tumor xenografts were recovered and analyzed by reverse phase protein array (RPPA). Analysis has revealed AKT pathway signaling alterations that underlie the enhanced response to cisplatin on addition of NU7441. DNA-PK inhibition is an attractive therapeutic strategy for resensitizing resistant tumors to platinum based therapy, directly linking the DNA damage caused by platinum to the pro-survival AKT pathway. This abstract is also presented as Poster A50. Citation Format: Azadeh Cheraghchi-Bashi-Astaneh, Camila H. De Sousa, Elaina Maginn, Yan Dai, Harpreet Wasan, Gordon B. Mills, Hani Gabra, Euan A. Stronach. DNA-PK inhibition resensitizes ovarian cancer cells to cisplatin in vivo and is associated with modulation of AKT pathway signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr PR04.