Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism
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
Affiliations
Elizabeth Bowler
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK
Anna Skwarska
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK
Joseph D. Wilson
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK
Shaliny Ramachandran
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK
Hannah Bolland
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK
Alistair Easton
Translational Histopathology Lab, Oxford Cancer Centre, Oxford OX3 7DQ, UK
Christian Ostheimer
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK
Ming-Shih Hwang
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK
Katarzyna B. Leszczynska
Oxford 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, Poland
Stuart J. Conway
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Ester M. Hammond
Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford OX3 7DQ, UK; Corresponding author
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.
