Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma

Cell Rep Med. 2023 Feb 21;4(2):100915. doi: 10.1016/j.xcrm.2022.100915. Epub 2023 Jan 18.


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.

Keywords: BAP1; EZH2; Polycomb; combination therapy; mesothelioma; mevalonate; preclinical models; targeted therapy; uveal melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol
  • Humans
  • Lung Neoplasms* / genetics
  • Mesothelioma* / genetics
  • Mesothelioma* / pathology
  • Mesothelioma, Malignant*
  • Mevalonic Acid
  • Mice
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism


  • Mevalonic Acid
  • Tumor Suppressor Proteins
  • Cholesterol
  • Ubiquitin Thiolesterase
  • BAP1 protein, human
  • BAP1 protein, mouse