Abstract 2604: The novel ATR inhibitor ATG-018 is efficacious in preclinical cancer models

Abstract

Abstract Background: The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DNA damage response (DDR) by activating essential signaling pathways of DNA damage repair. Inhibiting normal ATR function leads to increasing accumulation of double-strand breaks (DSB), particularly in genomically unstable tumor cells with preexisting replication stress, resulting in further genomic instability, mitotic catastrophe, and cell death. Targeting ATR is, therefore, a relevant strategy for the development of novel anticancer agents. This study tested the antitumor effects induced by ATG-018, a novel small molecule ATR inhibitor, in preclinical tumor models. Methods: Firstly, the antiproliferative activity of ATG-018 was evaluated against a panel of 143 tumor cell lines. Cell proliferation was measured after 72 hours of exposure to ATG-018, using CellTiter-Glo Cell Viability Assay. An unbiased genomic analysis of the tested cell lines was used to discover potential predictive biomarkers. The activity of ATR-inhibition by ATG-018 was determined by measuring phospho-Ser345 CHK1 protein level in HT-29 cells, using pCHK1 AlphaScreen assay. A mobility shift-based ATR kinase reaction assay was used to assess the direct inhibition of ATR by ATG-018. The in vivo anti-tumor efficacy of ATG-018 was evaluated in LoVo (colorectal cancer), OE21 (esophageal cancer) and OCI-LY-19 (lymphoma) CDX mouse models, respectively. Results: Potent in vitro and in vivo anti-tumor efficacy has been observed for ATG-018. For cell proliferation inhibition, the IC50 of ATG-018 ranged from 0.22μM to 10μM in 137 out of 143 cell lines, including both solid tumor and hematological malignancies, while ATG-018 did not affect the viability of normal PBMCs. A series of genetic alterations has been discovered to be correlated with the sensitivity to ATG-018, which could be potential predictive biomarkers. For ATR activity inhibition, the IC50 of ATG-018 required for ATR downstream (CHK1) phosphorylation inhibition was 1.4nM in HT-29 cells and the IC50 required for inhibiting ATR kinase reaction was 16nM. Dose-dependent antitumor efficacy was observed with ATG-018 in LoVo, OE21 and OCI-LY-19 CDX models. 10 mg/kg ATG-018 showed a statistically significant antitumor activity in all the three CDX models. In the OCI-LY-19 CDX model, 10 mg/kg ATG-018 showed 73.52% TGI on day 14 after grouping (p value=0.0014), and 50mg/kg ATG-018 induced tumor regression. Conclusions: Single agent ATG-018 exhibited strong monotherapy efficacy in preclinical cancer models with certain homologous recombination deficiencies, suggesting a promising therapeutic strategy for such patient populations. Citation Format: Hui Yuwen, Ya Kong, Lulu Jiang, Min Deng, Jiamei Luo, Bin Jiang, Bing Hou, Bo Shan, Jay Mei. The novel ATR inhibitor ATG-018 is efficacious in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2604.