Premium
Adefovir dipivoxil induces DNA replication stress and augments ATR inhibitor‐related cytotoxicity
Author(s) -
Patel Agata,
Seraia Elena,
Ebner Daniel,
Ryan Anderson Joseph
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32966
Subject(s) - dna damage , dna replication , biology , microbiology and biotechnology , dna repair , adefovir , kinase , chek1 , dna replication factor cdt1 , cell cycle , dna , cell , eukaryotic dna replication , cell cycle checkpoint , biochemistry , genetics , hepatitis b virus , virus , lamivudine
Replication stress is a common feature of cancer cells. Ataxia telangiectasia‐mutated (ATM) and Rad3‐related (ATR) signalling, a DNA damage repair (DDR) pathway, is activated by regions of single‐stranded DNA (ssDNA) that can arise during replication stress. 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‐dependant protein kinase (DNA‐PK) 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‐nuclear γH2AX‐positive cells, ssDNA accumulation and cell death, indicative of replication catastrophe.