Preclinical Characterization Of Vx-984, A Selective Dna-Dependent Protein Kinase (Dna-Pk) Inhibitor In Combination With Doxorubicin In Breast And Ovarian Cancers

Background: The efficacy of chemotherapeutic agents such as doxorubicin, which cause lethal DNA double-strand breaks (DSBs), is diminished by efficient repair of the damaged DNA in cancer cells. DNA-PK is a key regulator of the non-homologous end joining (NHEJ) pathway, which is responsible for repairing DSBs. Studies of nonselective inhibitors of DNA-PK have shown that cancer cells depend on DNA-PK for survival following treatment with DSB-inducing agents. However, a comprehensive characterization of DNA-PK inhibition has been hampered by a lack of selective inhibitors. Here we describe VX-984, a potent and selective inhibitor of DNA-PK, and its preclinical profile in combination with doxorubicin both in vitro and in vivo. Methods: VX-984 was examined as a single agent and in combination with doxorubicin or pegylated liposomal doxorubicin (PLD) in a panel of breast cancer cell lines and in mouse xenograft models, respectively. Results: In vitro, inhibition of DNA-PK by VX-984 enhanced the cytotoxic activity of doxorubicin in established breast cancer cell lines and in primary ovarian tumor explants. Notably, mean Bliss DE u003e10% (strong synergy) were observed for doxorubicin in the presence of VX-984 in 22 of 35 breast cancer cell lines and 21 of 44 ovarian cancer cell lines in a broad cancer cell line screen. Further, the efficacy observed with VX-984 was associated with increased DNA damage as measured by phosphorylated histone H2AX (gamma-H2AX) and phosphorylated Kruppel-associated protein (pKAP1) in DU4475, MDA-MB-436 and MDA-MB-468 breast cancer cell lines, which is consistent with diminished DSB repair. In vivo, VX-984 significantly enhanced the efficacy of PLD in ovarian cancer patient-derived xenograft models and in cell line xenograft models. Conclusions: These data provide evidence that inhibition of DNA-PK by VX-984 enhances the efficacy of doxorubicin in preclinical models and support the use of VX-984 in combination with DSB agents such as anthracyclines including PLD for the treatment of breast and ovarian cancers. VX-984 is currently in a Phase 1 clinical trial in combination with PLD. Sponsored by Vertex Pharmaceuticals Incorporated. Citation Format: Boucher D, Newsome D, Takemoto D, Hillier S, Wang Y, Arimoto R, Maxwell J, Charifson P, Fields SZ, Tanner K, Penney MS. Preclinical characterization of VX-984, a selective DNA-dependent protein kinase (DNA-PK) inhibitor in combination with doxorubicin in breast and ovarian cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-05.