Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma

Our plain-English summary of Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma, by G.K. Pandey, N. Landman, H.K. Neikes, et al (Cell Reports. Medicine, 2023).

The study

• Authors: G.K. Pandey, N. Landman, H.K. Neikes, D. Hulsman, C. Lieftink, R. Beijersbergen, K.K. Kolluri, S.M. Janes, M. Vermeulen, J. Badhai, M. van Lohuizen
• Journal: Cell Reports. Medicine
• Published: 2023;4(2):100915
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study searched for drug targets specific to mesothelioma cells lacking the BAP1 tumour-suppressor gene; the authors describe mesothelioma as linked to asbestos exposure. In a CRISPR-Cas9 dropout screen of 713 mouse kinases, six kinases were significantly depleted in Bap1-deficient BNC cells compared with Bap1-proficient NC cells, including two mevalonate pathway kinases, Mvk and Pmvk; both were also negatively selected in a BNCP line that additionally lacks Trp53. Bap1-deficient mouse and BAP1-mutant human mesothelioma cells were more sensitive to the mevalonate pathway inhibitor zoledronic acid than BAP1-proficient cells, and EZH2 inhibition raised cholesterol-metabolism gene expression only in BAP1-deficient cells. In a published cohort of 197 patients, the top quartile of mevalonate pathway gene expression had poorer survival than the bottom quartile (p = 0.0011); high MVK expression likewise (p = 0.004). In autochthonous Bap1-deficient mice, combined zoledronic acid plus tazemetostat gave median survival of 95 days versus 70 days for vehicle, 74 for zoledronic acid and 72 for tazemetostat alone.

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: Preclinical laboratory study: CRISPR-Cas9 kinome dropout screen in mouse mesothelioma cell lines, with cell-line drug assays, chromatin and expression analyses, analysis of a published patient survival dataset, and mouse xenograft and autochthonous tumour experiments
• Who was studied: Three mouse mesothelioma cell lines (NC; BNC; BNCP, which additionally lacks Tp53) derived from genetically engineered mouse models; human mesothelioma and uveal melanoma cell lines; NOD-Scid IL2Rgnull mice bearing xenografts (n = 8 per treatment group) and autochthonous Bap1-deficient mesothelioma mice (n = 11 per treatment group); plus a published cohort of 197 patients with mesothelioma for survival analysis
• Exposure: Not an environmental exposure study: the variable studied was BAP1/Bap1 loss combined with genetic knockout of kinases and with drugs, mainly zoledronic acid (mevalonate pathway) and the EZH2/PRC2 inhibitors GSK126 and tazemetostat; in mice, zoledronic acid 0.1 mg/kg every other day (xenografts) or 0.2 mg/kg once daily (autochthonous), tazemetostat 250 mg/kg
• Main results:
  • Six kinases were significantly depleted in Bap1-deficient (BNC) cells compared with Bap1-proficient (NC) cells, with Mvk and Pmvk among the top hits
  • Mvk and Pmvk were also negatively selected in the BNCP line, which lacks Trp53 in addition to Bap1
  • In colony-formation assays, Bap1-deficient mouse cell lines were more sensitive to zoledronic acid than the Bap1 wild-type line
  • In the 197-patient mesothelioma cohort, the quartile with highest mevalonate pathway gene expression had poorer survival than the lowest quartile
  • High MVK expression in the same patient cohort was associated with poor survival
  • EZH2 inhibition raised cholesterol metabolism gene expression only in BAP1-deficient cells
  • In xenografted mice, the drug combination inhibited growth of Bap1-deficient but not Bap1-proficient tumours
  • In autochthonous Bap1-deficient mesothelioma mice, median survival was 95 days with the combination versus 70 days with vehicle
  • The single agents gave 72 days (tazemetostat) and 74 days (zoledronic acid) median survival in the same mouse experiment
• The authors' conclusion: The authors concluded that BAP1 loss deregulates epigenetic and metabolic pathways and that simultaneously inhibiting PRC2 and the mevalonate pathway might be an attractive strategy for BAP1-deficient mesothelioma, to be evaluated in phase I/II studies
• Limitations the authors state:
  • Findings come from preclinical models, and tolerability, efficacy and pharmacokinetics may differ in patients
  • The ChIP sequencing signal was not experimentally quantified because spike-in chromatin was unavailable
  • The mechanism by which BAP1-deficient cells are sensitive to mevalonate pathway inhibition remains to be identified

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.

Related studies

• Combined Inhibition of EZH2 and FGFR is Synergistic in BAP1-deficient Malignant Mesothelioma — J. Badhai, N. Landman, et al. (2024)
• Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma — N. Landman, D. Hulsman, et al. (2024)
• 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)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma — J.N. Kuznetsoff, D.A. Owens, et al. (2021)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)

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