eLife (Jan 2018)
Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells
- Krishna Kalyan Kolluri,
- Constantine Alifrangis,
- Neelam Kumar,
- Yuki Ishii,
- Stacey Price,
- Magali Michaut,
- Steven Williams,
- Syd Barthorpe,
- Howard Lightfoot,
- Sara Busacca,
- Annabel Sharkey,
- Zhenqiang Yuan,
- Elizabeth K Sage,
- Sabarinath Vallath,
- John Le Quesne,
- David A Tice,
- Doraid Alrifai,
- Sylvia von Karstedt,
- Antonella Montinaro,
- Naomi Guppy,
- David A Waller,
- Apostolos Nakas,
- Robert Good,
- Alan Holmes,
- Henning Walczak,
- Dean A Fennell,
- Mathew Garnett,
- Francesco Iorio,
- Lodewyk Wessels,
- Ultan McDermott,
- Samuel M Janes
Affiliations
- Krishna Kalyan Kolluri
- ORCiD
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- Constantine Alifrangis
- ORCiD
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Neelam Kumar
- ORCiD
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- Yuki Ishii
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- Stacey Price
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Magali Michaut
- ORCiD
- The Netherlands Cancer Institute, Amsterdam, Netherlands
- Steven Williams
- ORCiD
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Syd Barthorpe
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Howard Lightfoot
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Sara Busacca
- CRUK Leicester Centre, Department of Cancer studies, University of Leicester, Leicester, United Kingdom
- Annabel Sharkey
- CRUK Leicester Centre, Department of Cancer studies, University of Leicester, Leicester, United Kingdom
- Zhenqiang Yuan
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- Elizabeth K Sage
- ORCiD
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- Sabarinath Vallath
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- John Le Quesne
- CRUK Leicester Centre, Department of Cancer studies, University of Leicester, Leicester, United Kingdom
- David A Tice
- Oncology Research, MedImmune, Inc., Gaithersburg, United States
- Doraid Alrifai
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- Sylvia von Karstedt
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, United Kingdom
- Antonella Montinaro
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, United Kingdom
- Naomi Guppy
- UCL Advanced Diagnostics, University College London, London, United Kingdom
- David A Waller
- Department of Thoracic Surgery, Glenfield Hospital, University Hospitals of Leicester, Leicester, United Kingdom
- Apostolos Nakas
- Department of Thoracic Surgery, Glenfield Hospital, University Hospitals of Leicester, Leicester, United Kingdom
- Robert Good
- UCL School of Pharmacy, University College London, London, United Kingdom
- Alan Holmes
- UCL School of Pharmacy, University College London, London, United Kingdom
- Henning Walczak
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, United Kingdom
- Dean A Fennell
- CRUK Leicester Centre, Department of Cancer studies, University of Leicester, Leicester, United Kingdom
- Mathew Garnett
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Francesco Iorio
- European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, United Kingdom
- Lodewyk Wessels
- The Netherlands Cancer Institute, Amsterdam, Netherlands
- Ultan McDermott
- Wellcome Trust Sanger Institute, Cambridge, United Kingdom
- Samuel M Janes
- ORCiD
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
- DOI
- https://doi.org/10.7554/eLife.30224
- Journal volume & issue
-
Vol. 7
Abstract
Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.
Keywords
