Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.

BACKGROUND: Up 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. METHODS: We 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. RESULTS: IC 50 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 IC 50 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.

AbstractBackgroundThe ataxia telangiectasia mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP ribose polymerase (PARP) inhibitor olaparib induced transient G2 arrest but not cell death in ATM-deficient A549 lung cancer cells, while the combination of olaparib with the ATM-, Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that the clinically relevant ATR inhibitor, AZD6738, sensitizes ATM-deficient A549 lung, prostate and pancreatic cancer cells to olaparib.MethodsATM was depleted from A549 lung cancer cells, PC-3 prostate cancer cells and Panc 10.05 pancreatic cancer cells, and the effects of olaparib alone and in combination with AZD6738 were determined.ResultsThe combination of olaparib plus AZD6738 induced cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts.ConclusionsLung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

The Ataxia Telangiectasia Mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP-ribose polymerase (PARP) inhibitor olaparib induces transient G2 arrest but not cell death in ATM-deficient lung cancer cells, while the combination of olaparib with the ATM-and Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that combination of olaparib plus the clinically relevant ATR inhibitor AZD6738 also induces cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts. Together, our data suggest that lung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

at the Guangdong Lung Cancer Institute. Both EGFR mutation and ALK rearrangement were tested by next-generation sequencing (NGS). Acquired ALK rearrangement was defined as positive ALK rearrangement after resistance to EGFR TKIs, but negative result detected by NGS at the baseline of EGFR TKI treatments. Result: Totally 320 patients were tested by NGS after resistance to EGFR TKIs (175, 42 and 103 with first-, second-and third-generation EGFR-TKIs respectively). Frequency of acquired ALK rearrangement was 1.14% (2/175), 2.38% (1/42) and 1.94% (2/103) in patients treated with first-, second-and third-generation EGFR TKIs respectively. The fusion partners of ALK were EML4 in 2 patients, CLIP4 (1), NPM1 (1) and PIBF1 (1). Non-EML4-ALK fusion accounted for 60%. One with acquired EML4-ALK achieved minor response with osimertinib plus crizotinib. One with acquired NPM1-ALK achieved partial response with erlotinib plus crizotinib. Unfortunately, one with acquired CLIP4-ALK fusion and BRAF V600E mutation did not respond to ensartinib single agent. One with acquired PIBF1-ALK had no clinical benefit with osimertinib plus alectinib. Finally, one with acquired EML4-ALK died shortly without any treatment due to poor performance status. Conclusion: The frequency of acquired ALK rearrangement is similar in EGFR-mutant lung adenocarcinomas after resistance to the first-, second-, or third-generation EGFR TKIs. The majority of acquired ALK-fusion partners are non-EML4. Combination of EGFR TKIs and ALK inhibitors might be a strategy to overcome such resistance.