Abstract 1388: ATM inhibitor AZD1390 sensitizes breast cancer brain metastasis to radiation therapy

Abstract

Abstract Metastasis to the central nervous system (CNS) has remained a major source of morbidity and mortality for patients with breast cancer. This is mainly driven by the lack of therapeutic options, as traditional chemotherapy and targeted therapies have been shown to have limited efficacy in the brain. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR.AZD1390 is a potent orally bioavailable ATM inhibitor, specifically optimized for blood brain barrier penetration and has shown to be an effective radiosensitizer in gliomas. We have shown that there are frequent alterations in DNA damage response (DDR) pathways in CNS metastasis (CM), which include frequent mutations in TP53. Incorrect repair of DNA lesions often leads to genomic instability. ATM, a core component of the DNA repair system, is activated to enhance the homologous recombination (HR) repair pathway upon DNA double-strand breaks. Here we show that AZD1390, when used in combination with radiation therapy, can inhibit the growth of breast cancer CM in patient derived xenograft (PDX) tumors. Three PDX models (2 Her2+ and one triple negative), all of which harbor TP53 mutations and other DDR alterations, were implanted into the flank or brain of immunocompromised mice. Pre-treatment with AZD1390 followed by a fractionated regime of radiation therapy (2Gy/day for 5 days) significantly inhibited growth of flank PDX tumors by an average of 81% (85% and 80% in the HER2+ and 77% in the triple negative PDX, p-value < 0.05). This is compared to an average of 7% (8%, 13% and 0% respectively) for tumors treated with AZD1390 alone or 40% (39%, 21% and 58% respectively) for radiation therapy alone in all PDX models. Growth inhibition was sustained until the experiment endpoint at 90 days in 75% of the tumors, and 25% of the tumors regressed below their size at the beginning of treatment. About 31% of tumors across three models started to grow back and gene expression analysis comparing these tumors with complete responders demonstrated changes in oxidative phosphorylation, sirtuin signaling, and ERK/MAPK signaling. Adjuvant therapy of AZD1390 did not further decrease tumor growth. Our results demonstrate that AZD1390 can sensitize breast cancer CM with DDR pathway alterations to radiation therapy. This points to the potential of AZD1390 as a potential novel therapeutic agent for patients with breast cancer CM. Citation Format: Ben Yi Tew, Stephen Durant, Bodour Salhia. ATM inhibitor AZD1390 sensitizes breast cancer brain metastasis to radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1388.