Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells

Our plain-English summary of Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells, by K.K. Kolluri, C. Alifrangis, N. Kumar, et al (eLife, 2018).

The study

• Authors: K.K. Kolluri, C. Alifrangis, N. Kumar, Y. Ishii, S. Price, M. Michaut, S. Williams, S. Barthorpe, H. Lightfoot, S. Busacca, A. Sharkey, Z. Yuan, E.K. Sage, S. Vallath, J. Le Quesne, D.A. Tice, D. Alrifai, S. von Karstedt, A. Montinaro, N. Guppy, D.A. Waller, A. Nakas, R. Good, A. Holmes, H. Walczak, D.A. Fennell, M. Garnett, F. Iorio, L. Wessels, U. McDermott, S.M. Janes
• Journal: eLife
• Published: 2018;7
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2017, Kolluri et al.

In plain English

This laboratory study tested 94 drugs, plus recombinant TRAIL (rTRAIL) at a fixed dose, on 15 exome-sequenced malignant mesothelioma (MM) cell lines. It looked for links between mutations in candidate MM driver genes and drug response. Of 24 associations reaching a false discovery rate below 0.2, the strongest sensitising association was between loss-of-function mutations in BAP1 and rTRAIL (FDR = 0.18). No sensitising association with BAP1 was seen for pemetrexed or cisplatin. In a wider panel, 6 of 8 BAP1 loss-of-function lines were sensitive or partially sensitive to rTRAIL, while 7 of 9 BAP1 wild-type lines were resistant. Silencing BAP1 increased sensitivity to rTRAIL in BAP1 wild-type MM, breast and renal carcinoma lines. Among 25 early passage MM cultures, those lacking strong nuclear BAP1 staining were more sensitive (p=0.0067). In tumour explants from three MM patients, rTRAIL caused more cleaved PARP, a marker of apoptosis, in low-BAP1 explants than in high-BAP1 explants. In mice, TRAIL-treated BAP1-mutant xenografts weighed less than TRAIL-treated wild-type xenografts (p=0.020). The authors concluded that BAP1 loss is a potential stratification biomarker for TRAIL sensitivity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: high-throughput drug screen in molecularly characterised cancer cell lines, with gene knockdown and construct experiments, human tumour explants and mouse xenografts
• Who was studied: Several groups of samples: 15 malignant mesothelioma cell lines in the screen (later a panel of 17); non-mesothelioma lines (breast MDAMB-231, renal Caki-1 and BB65); 25 human early passage MM cultures from MesobanK UK; tumour explants from three MM patients; and 12 NOD SCID mice
• Exposure: 94 anti-cancer compounds screened across 5-point dose ranges, plus recombinant TRAIL (rTRAIL) at a fixed 40 ng/ml in the screen; later experiments also used the death receptor 5 superagonist MEDI3039. Cells were classified by BAP1 mutation or expression status. The authors describe mesothelioma as associated with asbestos exposure, but asbestos was not studied
• Main results:
  • In the 15-line screen, 24 associations between drug response and genomic alteration reached FDR below 0.2. The strongest sensitising one was BAP1 loss-of-function with rTRAIL (FDR = 0.18). The sign of the printed effect size is lost in the text
  • In a larger MM cell line panel, 6 of 8 BAP1 loss-of-function lines were sensitive or partially sensitive to rTRAIL, and 7 of 9 BAP1 wild-type lines were resistant
  • No sensitising association with BAP1 status was seen for the first-line mesothelioma drugs pemetrexed or cisplatin
  • Silencing BAP1 in four BAP1 wild-type MM cell lines increased cell death after rTRAIL compared with control shRNA and the parent lines
  • Knockdown of BAP1 in two clear cell renal carcinoma lines and in the MDAMB-231 breast cancer line increased sensitivity to rTRAIL
  • In BAP1-null H226 cells, adding wild-type BAP1 reduced rTRAIL sensitivity, as did all the mutant constructs except those lacking deubiquitinase activity or the ASXL-binding site
  • H226 cells given the C91A BAP1 mutant were rTRAIL-sensitive; compared with cells given wild-type BAP1, they had lower mRNA levels of anti-apoptotic cIAP1/2 and higher levels of pro-apoptotic death receptor 5
  • Among 25 early passage MM cultures, those without strong nuclear BAP1 staining were more rTRAIL-sensitive. Of the 12 lines without nuclear BAP1, 9 were sensitive, 2 partially sensitive and 1 resistant
  • In tumour explants from three MM patients, rTRAIL produced more apoptosis (cleaved PARP) in explants with low BAP1 expression than in those with high BAP1 expression
  • In mouse xenografts, rTRAIL-treated BAP1-mutant (C91A) tumours weighed less than rTRAIL-treated wild-type tumours (p=0.020) and vehicle-treated mutant tumours (p=0.019). Wild-type tumours did not respond
• The authors' conclusion: The authors concluded that loss of BAP1 function may serve as a genomic stratification tool to identify rTRAIL-sensitive mesothelioma tumours, possibly also in other cancer types. They proposed transcriptional regulation by the PR-DUB complex as the mechanism
• Limitations the authors state:
  • The authors stated that no single factor explaining BAP1-induced TRAIL resistance could be identified
  • The authors stated that the clinical value of BAP1 as a targeting biomarker still needs confirmation in early phase clinical trials in mesothelioma
  • The authors noted that H513, a line on the list of commonly misidentified cell lines, was included in the 15-line screen but not used in later experiments

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma, Chemotherapy, Discovery, Necrosis, Apoptosis, Biomarker.

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• Loss of BAP1 function leads to EZH2-dependent transformation — L.M. LaFave, W. Béguelin, et al. (2015)
• Membrane-bound TRAIL-armoring augments CAR-T cells in mesothelin-positive solid malignancies — A. Volpe, J. Zurita, et al. (2026)
• Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors — J.J. Sacco, J. Kenyani, et al. (2015)
• Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition — A. Okonska, S. Bühler, et al. (2020)
• Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth — R.G. van der Most, A.J. Currie, et al. (2009)

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