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      Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells

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          Abstract

          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.

          Conclusions

          Patients with tumours characterised by ATM-deficiency may benefit from treatment with a PARP inhibitor in combination with an ATR inhibitor.

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          Most cited references46

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            Poly(ADP-ribose): novel functions for an old molecule.

            The addition to proteins of the negatively charged polymer of ADP-ribose (PAR), which is synthesized by PAR polymerases (PARPs) from NAD(+), is a unique post-translational modification. It regulates not only cell survival and cell-death programmes, but also an increasing number of other biological functions with which novel members of the PARP family have been associated. These functions include transcriptional regulation, telomere cohesion and mitotic spindle formation during cell division, intracellular trafficking and energy metabolism.
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              Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.

              Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
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                Author and article information

                Contributors
                +1-403-220-7628 , leesmill@ucalgary.ca
                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                4 September 2019
                1 October 2019
                : 121
                : 7
                : 600-610
                Affiliations
                [1 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Departments of Biochemistry and Molecular Biology, , Robson DNA Science Centre and Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, ; 3330 Hospital Drive NW, Calgary, Alberta T2N 1N4 Canada
                [2 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Department Oncology, , Robson DNA Science Centre and Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, ; 3330 Hospital Drive NW, Calgary, Alberta T2N 1N4 Canada
                Article
                565
                10.1038/s41416-019-0565-8
                6889280
                31481733
                93cd7ac7-83c7-4013-893f-209b074d1941
                © The Author(s), under exclusive licence to Cancer Research UK 2019

                This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

                History
                : 7 March 2019
                : 19 June 2019
                : 21 June 2019
                Funding
                Funded by: Ohlson Research Initiative, Charbonneau Cancer Institute, Calgary, Alberta, Canada
                Funded by: FundRef https://doi.org/10.13039/100009326, Cancer Research Society (Société de Recherche sur le Cancer);
                Award ID: 20229
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: P01 CA92584
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000024, Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada);
                Award ID: MOP13639
                Award Recipient :
                Funded by: Alberta Cancer Foundation/Engineered Air Chair in Cancer Research # 21202
                Categories
                Article
                Custom metadata
                © Cancer Research UK 2019

                Oncology & Radiotherapy
                cancer,non-small-cell lung cancer,lung cancer
                Oncology & Radiotherapy
                cancer, non-small-cell lung cancer, lung cancer

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