Abstract LB-107: Targeting ATR using a novel ATR inhibitor AZD6738 in human gastric cancer cells

Abstract

Abstract Introduction: The DNA repair system is critical for maintaining genomic integrity. In particular, the homologous recombination (HR) repair pathway, on that repairs DNA double-strand breaks (DSBs), is directly associated with cancer development. Many cancer cells could contain mutations in genes involved in the HR pathway including BRCA1/2, ATM, ATR, and RAD51. ATR can be activated by various types of DNA damage and it initiates DNA damage-induces signaling cascade. As a result, ATR pathway components are considered promising therapeutic targets because ATR inhibition is likely to have greater deleterious effect on cancer cells. Materials and Methods: The antiproliferative activity of AZD6738 was examined in vitro using a cytotoxic assay, cell cycle analysis, and western blotting. To figure out the action mechanism of AZD6738 in gastric cancer cells, the expression of proteins which participate in DNA repair were investigated. The accumulation of DNA damage was also assessed with a DNA comet assay. These in vitro data were validated in vivo using a human gastric cancer xenograft model. Results: Human gastric cancer cell lines showed heterogeneous response to AZD6738. In AZD6738 sensitive cells, ATR inhibition leads to the accumulation of unrepaired DSBs due to dysfunctional RAD51 foci formation along with increased caspase 3-dependent cell death and S phase cell cycle arrest. Compared with sensitive cells, the activation of ATM-chk2 signaling pathway under the ATR inhibition was observed in the AZD6738 insensitive cells. It suggests that the activation of ATM-chk2 signal leads to attenuation of AZD6738 sensitivity. Furthermore, AZD6738 significantly suppressed tumor growth with increased apoptosis in vivo. Conclusion: We evaluated the anti-tumor activity of AZD6738 in gastric cancer in vitro and in vivo model. This is the first study to show that AZD6738 interferes with RAD51-mediated homologous recombination, as well as promotes cell death by inducing S cell cycle arrest and apoptosis in gastric cancer cells. Our findings can help to promote novel treatment strategies using AZD6738 in gastric cancer. Citation Format: Ahrum Min, Seock-Ah Im, Hyemin Jang, Seongyeong Kim, Miso Lee, Jungeun Kim, Kyung-Hun Lee, Sae-Won Han, Tae-Young Kim, Do-Youn Oh, Tae-You Kim, Woo-Ho Kim, Yung-Jue Bang. Targeting ATR using a novel ATR inhibitor AZD6738 in human gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-107. doi:10.1158/1538-7445.AM2015-LB-107