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ATR delays cell cycle progression and prevents DNA replication fork collapse, which prohibits cell death and promotes proliferation. Several ATR inhibitors have been developed in order to restrain this protective mechanism in tumours. It is known, however, that despite other effective anticancer chemotherapy treatments targeting DDR pathways, resistance occurs. This begets the need to identify combination treatments to overcome resistance and prevent tumour cell growth. We conducted a drug screen to identify potential synergistic combination treatments by screening an ATR inhibitor (VE822) together with compounds from a bioactive small molecule library. The screen identified adefovir dipivoxil, a reverse transcriptase inhibitor and nucleoside analogue, as a compound that has increased cytotoxicity in the presence of ATR, but not ATM or DNA\u2010dependant protein kinase (DNA\u2010PK) inhibition. Here we demonstrate that adefovir dipivoxil induces DNA replication stress, activates ATR signalling and stalls cells in S phase. This simultaneous induction of replication stress and inhibition of ATR signalling lead to a marked increase in pan\u2010nuclear \u03b3H2AX\u2010positive cells, ssDNA accumulation and cell death, indicative of replication catastrophe.<\/jats:p>","DOI":"10.1002\/ijc.32966","type":"journal-article","created":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T13:07:51Z","timestamp":1583932071000},"page":"1474-1484","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Adefovir dipivoxil induces DNA replication stress and augments ATR inhibitor\u2010related cytotoxicity"],"prefix":"10.1002","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3429-4847","authenticated-orcid":false,"given":"Agata","family":"Patel","sequence":"first","affiliation":[{"name":"The Department of Oncology, Oxford Institute for Radiation Oncology University of Oxford  Oxford United 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