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Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells

Kolluri, KK; Alifrangis, C; Kumar, N; Ishii, Y; Price, S; Michaut, M; Williams, S; ... Janes, SM; + view all (2018) Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. eLIFE , 7 , Article e30224. 10.7554/eLife.30224. Green open access

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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.

Type: Article
Title: Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.7554/eLife.30224
Publisher version: http://dx.doi.org/10.7554/eLife.30224
Language: English
Additional information: Copyright © Kolluri et al. 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.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biology, Life Sciences & Biomedicine - Other Topics, MALIGNANT PLEURAL MESOTHELIOMA, APOPTOSIS-INDUCING LIGAND, LUNG-CANCER, BRCA1-ASSOCIATED PROTEIN-1, DEUBIQUITINASE COMPLEX, UBIQUITIN HYDROLASE, MONOCLONAL-ANTIBODY, FREQUENT MUTATION, MYELOID-LEUKEMIA, TUMOR-SUPPRESSOR
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Metabolism and Experi Therapeutics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10042318
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