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Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma

Gaurav Kumar Pandey1, Nick Landman1, Hannah K Neikes2

  • 1Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands.

Cell Reports. Medicine
|January 19, 2023
PubMed

Insights

Loss of the BAP1 tumor suppressor gene in mesothelioma creates vulnerabilities. Targeting the mevalonate pathway and Polycomb repressive complex 2 (PRC2) shows potent anti-tumor effects in preclinical models.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Therapeutics

Background:

  • Alterations in the BAP1 tumor-suppressor gene are common in malignant mesothelioma.
  • BAP1 loss, as part of the Polycomb repressive deubiquitinating (PR-DUB) complex, impacts the epigenome and may confer drug sensitivities.
  • The specific vulnerabilities arising from BAP1 deficiency in mesothelioma are not well understood.

Purpose of the Study:

  • To identify novel therapeutic vulnerabilities in BAP1-deficient malignant mesothelioma.
  • To investigate the role of the epigenome, specifically Polycomb repressive complex 2 (PRC2), in BAP1-mutated mesothelioma.
  • To evaluate a combination therapy targeting the mevalonate pathway and PRC2 in mesothelioma.

Main Methods:

  • Conducted a CRISPR-Cas9 kinome screen in mesothelioma cells to identify key kinases.
  • Analyzed chromatin, gene expression, and genetic perturbation data in mesothelioma cell lines.
  • Utilized pharmacological inhibitors of PRC2 (tazemetostat) and the mevalonate pathway (zoledronic acid) in cell lines and preclinical mouse models (autochthonous Bap1-deficient mesothelioma and xenografts).

Main Results:

  • The kinome screen identified kinases within the mevalonate/cholesterol biosynthesis pathway.
  • Mesothelioma cells showed a dependency on PRC2-mediated gene silencing.
  • Inhibition of PRC2 upregulated cholesterol biosynthesis genes specifically in BAP1-deficient mesothelioma, sensitizing them to combined PRC2 and mevalonate pathway inhibition.
  • Combined inhibition demonstrated a potent anti-tumor effect in preclinical models of BAP1-deficient mesothelioma.

Conclusions:

  • BAP1-deficient mesothelioma exhibits specific dependencies on the mevalonate pathway and PRC2.
  • Combined pharmacological targeting of PRC2 and the mevalonate pathway represents a promising therapeutic strategy for BAP1-deficient mesothelioma.
  • This study highlights a novel therapeutic window for BAP1-mutated cancers.
Keywords:
BAP1EZH2Polycombcombination therapymesotheliomamevalonatepreclinical modelstargeted therapyuveal melanoma

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