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

doi:10.7554/eLife.30224

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 GuppyDavid A Waller, Apostolos Nakas, Robert Good, Alan Holmes, Henning Walczak, Dean A Fennell, Mathew Garnett, Francesco Iorio, Lodewyk Wessels, Ultan McDermott, Samuel M Janes

Applied Health Sciences

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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.

Original language	English
Article number	e30224
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.30224
Publication status	Published - 18 Jan 2018

Bibliographical note

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.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.30224Licence: CC BY

Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
Final published version, 2.99 MBLicence: CC BY

Cite this

Kolluri, K. K., Alifrangis, C., Kumar, N., Ishii, Y., Price, S., Michaut, M., Williams, S., Barthorpe, S., Lightfoot, H., Busacca, S., Sharkey, A., Yuan, Z., Sage, E. K., Vallath, S., Le Quesne, J., Tice, D. A., Alrifai, D., von Karstedt, S., Montinaro, A., ... Janes, S. M. (2018). Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. eLife, 7, Article e30224. https://doi.org/10.7554/eLife.30224

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

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title = "Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells",

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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author = "Kolluri, {Krishna Kalyan} and Constantine Alifrangis and Neelam Kumar and Yuki Ishii and Stacey Price and Magali Michaut and Steven Williams and Syd Barthorpe and Howard Lightfoot and Sara Busacca and Annabel Sharkey and Zhenqiang Yuan and Sage, {Elizabeth K} and Sabarinath Vallath and {Le Quesne}, John and Tice, {David A} and Doraid Alrifai and {von Karstedt}, Sylvia and Antonella Montinaro and Naomi Guppy and Waller, {David A} and Apostolos Nakas and Robert Good and Alan Holmes and Henning Walczak and Fennell, {Dean A} and Mathew Garnett and Francesco Iorio and Lodewyk Wessels and Ultan McDermott and Janes, {Samuel M}",

note = "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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T1 - Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells

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.

PY - 2018/1/18

Y1 - 2018/1/18

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.

AB - 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.

KW - Animals

KW - Cell Line, Tumor

KW - Humans

KW - Lung Neoplasms/physiopathology

KW - Mesothelioma/physiopathology

KW - Mice

KW - Repressor Proteins/metabolism

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

M3 - Article

C2 - 29345617

VL - 7

JO - eLife

JF - eLife

M1 - e30224

ER -

Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells

Abstract

Bibliographical note

Keywords

UN SDGs

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