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Updated: Jun 30, 2025

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma

Nick Landman1,2, Danielle Hulsman1,2, Jitendra Badhai1,2

  • 1Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.

British Journal of Cancer
|March 23, 2024
PubMed
Abstract

Insights

Combining EZH2 inhibition with ATM inhibition shows promise for treating BAP1-deficient mesothelioma. This combination therapy may improve efficacy and overcome resistance in mesothelioma patients with BAP1 alterations.

Area of Science:

  • Oncology
  • Cancer Genetics
  • Drug Discovery

Background:

  • Over 50% of mesothelioma tumors exhibit alterations in the BAP1 tumor suppressor gene.
  • BAP1-deficient mesothelioma shows preclinical sensitivity to EZH2 inhibition, but clinical efficacy is modest.
  • Combination therapy may enhance EZH2 inhibition efficacy and prevent acquired resistance.

Purpose of the Study:

  • To identify novel combination therapies for BAP1-deficient mesothelioma.
  • To evaluate the synergistic potential of EZH2 inhibition combined with other anti-cancer agents.

Main Methods:

  • A drug synergy screen of 20 compounds combined with EZH2 inhibition was performed in mesothelioma cell lines.
  • Synergistic potential was assessed using the Bliss model.
  • In vivo xenograft experiments validated the findings.

Main Results:

  • Combining EZH2 inhibition with ATM inhibition (ATMi) demonstrated synergistic potential against BAP1-deficient mesothelioma.
  • This combination significantly enhanced tumor growth inhibition in preclinical models.
  • Lower ATM levels were observed upon BAP1 depletion, potentially mediated by E2F1.

Conclusions:

  • The combination of ATM and EZH2 inhibition is effective against BAP1-deficient mesothelioma in preclinical models.
  • This combination represents a potential novel treatment strategy for mesothelioma.
  • BAP1 can serve as a predictive biomarker for this targeted therapy.

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