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

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10 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

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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