Abstract
BackgroundUp to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression. We asked whether ATM-deficient lung cancer cell lines are sensitive to poly-ADP ribose polymerase (PARP) inhibitors and determined the mechanism of action of olaparib in ATM-deficient A549 cells.MethodsWe analysed drug sensitivity data for olaparib and talazoparib in lung adenocarcinoma cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) project. We deleted ATM from A549 lung adenocarcinoma cells using CRISPR/Cas9 and determined the effects of olaparib and the ATM/Rad3-related (ATR) inhibitor VE-821 on cell viability.ResultsIC50 values for both olaparib and talazoparib positively correlated with ATM mRNA levels and gene amplification status in lung adenocarcinoma cell lines. ATM mutation was associated with a significant decrease in the IC50 for olaparib while a similar trend was observed for talazoparib. A549 cells with deletion of ATM were sensitive to ionising radiation and olaparib. Olaparib induced phosphorylation of DNA damage markers and reversible G2 arrest in ATM-deficient cells, while the combination of olaparib and VE-821 induced cell death.ConclusionsPatients with tumours characterised by ATM-deficiency may benefit from treatment with a PARP inhibitor in combination with an ATR inhibitor.
Highlights
Up to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression
Cells with defects in genes required for repair of DNA double-strand breaks (DSBs) via the homologous recombination repair (HRR) pathway are exquisitely sensitive to poly-ADP ribose polymerase (PARP) inhibitors,[1,2] and the PARP inhibitors olaparib, rucaparib and niraparib have been approved for use in patients with BRCA-deficient breast and/or ovarian cancers, while talazoparib and veliparib are in clinical trials.[3,4,5,6]
To empirically test whether olaparib can target ATM-deficient human cell lines, we used CRISPR/Cas[9] to deplete ATM and DNAPKcs from A549 cells, a human lung adenocarcinoma cell line, and used these cells to interrogate the mechanism by which lung adenocarcinoma cells respond to olaparib
Summary
Up to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression. We previously showed that ATM-deficient MCL,[22,23] colorectal[24] and gastric cancer[25] cell lines with depletion or inhibition of ATM are sensitive to olaparib, especially when accompanied by loss or mutation of TP53.22,24,25 We demonstrated that relative loss of ATM has clinical implications, conferring worse outcome and associated with improved benefit from cisplatin therapy.[26]
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