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 & 11 others 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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Article numbere30224
JournaleLife
Volume7
DOIs
Publication statusPublished - 18 Jan 2018

Fingerprint

Cells
Association reactions
Neoplasms
Death Domain Receptors
Proteins
Chemotherapy
Biomarkers
Exome
Heterografts
Tumors
Tumor Necrosis Factor-alpha
Modulation
Apoptosis
Ligands
Drug Therapy
Pharmaceutical Preparations
Mutation
Malignant Mesothelioma
Therapeutics
Deubiquitinating Enzymes

Keywords

  • Animals
  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms/physiopathology
  • Mesothelioma/physiopathology
  • Mice
  • Repressor Proteins/metabolism
  • TNF-Related Apoptosis-Inducing Ligand/metabolism
  • Tumor Suppressor Proteins/metabolism
  • Ubiquitin Thiolesterase/metabolism

Cite this

Kolluri, K. K., Alifrangis, C., Kumar, N., Ishii, Y., Price, S., Michaut, M., ... Janes, S. M. (2018). Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. eLife, 7, [e30224]. https://doi.org/10.7554/eLife.30224

Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. / Kolluri, Krishna Kalyan; Alifrangis, Constantine; Kumar, Neelam; Ishii, Yuki; Price, Stacey; Michaut, Magali; Williams, Steven; Barthorpe, Syd; Lightfoot, Howard; Busacca, Sara; Sharkey, Annabel; Yuan, Zhenqiang; Sage, Elizabeth K; Vallath, Sabarinath; Le Quesne, John; Tice, David A; Alrifai, Doraid; von Karstedt, Sylvia; Montinaro, Antonella; Guppy, Naomi; Waller, David A; Nakas, Apostolos; Good, Robert; Holmes, Alan; Walczak, Henning; Fennell, Dean A; Garnett, Mathew; Iorio, Francesco; Wessels, Lodewyk; McDermott, Ultan; Janes, Samuel M.

In: eLife, Vol. 7, e30224, 18.01.2018.

Research output: Contribution to journalArticle

Kolluri, KK, Alifrangis, C, Kumar, N, Ishii, Y, Price, S, Michaut, M, Williams, S, Barthorpe, S, Lightfoot, H, Busacca, S, Sharkey, A, Yuan, Z, Sage, EK, Vallath, S, Le Quesne, J, Tice, DA, Alrifai, D, von Karstedt, S, Montinaro, A, Guppy, N, Waller, DA, Nakas, A, Good, R, Holmes, A, Walczak, H, Fennell, DA, Garnett, M, Iorio, F, Wessels, L, McDermott, U & Janes, SM 2018, 'Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells', eLife, vol. 7, e30224. https://doi.org/10.7554/eLife.30224
Kolluri KK, Alifrangis C, Kumar N, Ishii Y, Price S, Michaut M et al. Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. eLife. 2018 Jan 18;7. e30224. https://doi.org/10.7554/eLife.30224
Kolluri, Krishna Kalyan ; Alifrangis, Constantine ; Kumar, Neelam ; Ishii, Yuki ; Price, Stacey ; Michaut, Magali ; Williams, Steven ; Barthorpe, Syd ; Lightfoot, Howard ; Busacca, Sara ; Sharkey, Annabel ; Yuan, Zhenqiang ; Sage, Elizabeth K ; Vallath, Sabarinath ; Le Quesne, John ; Tice, David A ; Alrifai, Doraid ; von Karstedt, Sylvia ; Montinaro, Antonella ; Guppy, Naomi ; Waller, David A ; Nakas, Apostolos ; Good, Robert ; Holmes, Alan ; Walczak, Henning ; Fennell, Dean A ; Garnett, Mathew ; Iorio, Francesco ; Wessels, Lodewyk ; McDermott, Ultan ; Janes, Samuel M. / Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. In: eLife. 2018 ; Vol. 7.
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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.",
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AU - Kolluri, Krishna Kalyan

AU - Alifrangis, Constantine

AU - Kumar, Neelam

AU - Ishii, Yuki

AU - Price, Stacey

AU - Michaut, Magali

AU - Williams, Steven

AU - Barthorpe, Syd

AU - Lightfoot, Howard

AU - Busacca, Sara

AU - Sharkey, Annabel

AU - Yuan, Zhenqiang

AU - Sage, Elizabeth K

AU - Vallath, Sabarinath

AU - Le Quesne, John

AU - Tice, David A

AU - Alrifai, Doraid

AU - von Karstedt, Sylvia

AU - Montinaro, Antonella

AU - Guppy, Naomi

AU - Waller, David A

AU - Nakas, Apostolos

AU - Good, Robert

AU - Holmes, Alan

AU - Walczak, Henning

AU - Fennell, Dean A

AU - Garnett, Mathew

AU - Iorio, Francesco

AU - Wessels, Lodewyk

AU - McDermott, Ultan

AU - Janes, Samuel M

N1 - Funding Wellcome (WT097452MA) Constantine Alifrangis Wellcome Trust (106555/Z/14/Z) Neelam Kumar Cancer Research UK (A17341) Henning Walczak Cancer Research UK Ultan McDermott Wellcome (WT107963AIA) Samuel M Janes The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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N2 - 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.

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KW - Cell Line, Tumor

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KW - Mesothelioma/physiopathology

KW - Mice

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KW - TNF-Related Apoptosis-Inducing Ligand/metabolism

KW - Tumor Suppressor Proteins/metabolism

KW - Ubiquitin Thiolesterase/metabolism

U2 - 10.7554/eLife.30224

DO - 10.7554/eLife.30224

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VL - 7

JO - eLife

JF - eLife

SN - 2050-084X

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