Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism
Summary: Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using f...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-11-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220308609 |
| _version_ | 1818558230375170048 |
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| author | Elizabeth Bowler Anna Skwarska Joseph D. Wilson Shaliny Ramachandran Hannah Bolland Alistair Easton Christian Ostheimer Ming-Shih Hwang Katarzyna B. Leszczynska Stuart J. Conway Ester M. Hammond |
| author_facet | Elizabeth Bowler Anna Skwarska Joseph D. Wilson Shaliny Ramachandran Hannah Bolland Alistair Easton Christian Ostheimer Ming-Shih Hwang Katarzyna B. Leszczynska Stuart J. Conway Ester M. Hammond |
| author_sort | Elizabeth Bowler |
| collection | DOAJ |
| description | Summary: Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy. |
| first_indexed | 2024-12-14T00:09:54Z |
| format | Article |
| id | doaj.art-9101f532972247d3b9744910af5a4602 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-14T00:09:54Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-9101f532972247d3b9744910af5a46022022-12-21T23:25:47ZengElsevieriScience2589-00422020-11-012311101668Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent MechanismElizabeth Bowler0Anna Skwarska1Joseph D. Wilson2Shaliny Ramachandran3Hannah Bolland4Alistair Easton5Christian Ostheimer6Ming-Shih Hwang7Katarzyna B. Leszczynska8Stuart J. Conway9Ester M. Hammond10Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UKTranslational Histopathology Lab, Oxford Cancer Centre, Oxford OX3 7DQ, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK; Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, PolandDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UKOxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK; Corresponding authorSummary: Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.http://www.sciencedirect.com/science/article/pii/S2589004220308609Biological SciencesBiochemistryBiochemical MechanismCancer |
| spellingShingle | Elizabeth Bowler Anna Skwarska Joseph D. Wilson Shaliny Ramachandran Hannah Bolland Alistair Easton Christian Ostheimer Ming-Shih Hwang Katarzyna B. Leszczynska Stuart J. Conway Ester M. Hammond Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism iScience Biological Sciences Biochemistry Biochemical Mechanism Cancer |
| title | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
| title_full | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
| title_fullStr | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
| title_full_unstemmed | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
| title_short | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
| title_sort | pharmacological inhibition of atr can block autophagy through an atr independent mechanism |
| topic | Biological Sciences Biochemistry Biochemical Mechanism Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220308609 |
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