ATM-inhibitor AZD1390 is a radiosensitizer for breast cancer CNS metastasis
Purpose: Central nervous system (CNS) metastasis has remained a major source of mortality for breast cancer patients. This is largely driven by the inability of current therapeutics to penetrate the blood brain barrier (BBB) and the lack of preclinical models for testing new therapies. Here we study the efficacy of AZD1390, a BBB penetrating ataxia-telangiectasia mutated (ATM) inhibitor, as a radiosensitizer for breast cancer CNS metastasis treatment. Experimental Design: Three PDX tumors including 2 HER2+ and 1 triple negative breast cancer (TNBC) harboring TP53 mutations, were implanted subcutaneously in the flank of mice to assess tumor growth inhibition by AZD1390 combined with radiation. Animal survival was further assessed by implanting the best responding PDX model orthotopically in the brain. Results: Pretreatment with AZD1390 followed by radiation therapy inhibited growth of PDX tumors implanted in the flank, and improved survival in orthotopic models with average survival 222 days compared to 123 days in controls. Adjuvant administration of AZD1390 had no further benefits. While the combination therapy resulted in sustained tumor inhibition, sporadic regrowth was observed in in some mice 50-100 days post-treatment in all models. Gene expression analysis comparing these tumors with complete responders demonstrated changes in upregulation of multiple oncogenic proteins, which are potential drivers of tumor growth after treatment. Conclusions: Our results demonstrate that AZD1390 effectively sensitizes breast cancer CNS metastasis to radiation therapy in TP53 mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CNS metastasis. Overall design: RNA-seq profiling of tumors after combiation of AZD1390 and radiation therapy