Pharmacological inhibition of ATR can block autophagy through an ATR-independent mechanism
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 i...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2020
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| _version_ | 1826295667952189440 |
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| author | Bowler, E Skwarska, A Wilson, JD Ramachandran, S Bolland, H Easton, A Ostheimer, C Hwang, M-S Leszczynska, KB Conway, SJ Hammond, EM |
| author_facet | Bowler, E Skwarska, A Wilson, JD Ramachandran, S Bolland, H Easton, A Ostheimer, C Hwang, M-S Leszczynska, KB Conway, SJ Hammond, EM |
| author_sort | Bowler, E |
| collection | OXFORD |
| description | 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 | 2024-03-07T04:04:35Z |
| format | Journal article |
| id | oxford-uuid:c5b7b0c7-49d5-41bf-b1c5-2db7b105bdff |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:04:35Z |
| publishDate | 2020 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:c5b7b0c7-49d5-41bf-b1c5-2db7b105bdff2022-03-27T06:33:07ZPharmacological inhibition of ATR can block autophagy through an ATR-independent mechanismJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c5b7b0c7-49d5-41bf-b1c5-2db7b105bdffEnglishSymplectic ElementsCell Press2020Bowler, ESkwarska, AWilson, JDRamachandran, SBolland, HEaston, AOstheimer, CHwang, M-SLeszczynska, KBConway, SJHammond, EMInhibition 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. |
| spellingShingle | Bowler, E Skwarska, A Wilson, JD Ramachandran, S Bolland, H Easton, A Ostheimer, C Hwang, M-S Leszczynska, KB Conway, SJ Hammond, EM Pharmacological inhibition of ATR can block autophagy through an ATR-independent mechanism |
| 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 |
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