title: ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A.
abstract: Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells.
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Williamson
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Rowan
authors.initials: R
authors.lastname: Miller
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Helen N
authors.initials: HN
authors.lastname: Pemberton
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Jones
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Asha
authors.initials: A
authors.lastname: Konde
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Badham
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Rumana
authors.initials: R
authors.lastname: Rafiq
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brough
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Aditi
authors.initials: A
authors.lastname: Gulati
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Colm J
authors.identifier: 0000-0003-2750-9854
authors.initials: CJ
authors.lastname: Ryan
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Jeff
authors.initials: J
authors.lastname: Francis
authors.affiliation: The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.|GZA Hospitals Sint-Augustinus, Wilrijk, Belgium and Center for Oncological Research, University of Antwerp, Oosterveldlaan 24, Wilrijk Antwerp 2610, Belgium.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Vermulen
authors.affiliation: The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Reynolds
authors.affiliation: Vertex Pharmaceuticals (Europe) Limited, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Reaper
authors.affiliation: Vertex Pharmaceuticals (Europe) Limited, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Pollard
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.|The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins