Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma

Gaurav Kumar Pandey, Nick Landman, Hannah K. Neikes, Danielle Hulsman, Cor Lieftink, Roderick Beijersbergen, Krishna Kalyan Kolluri, Sam M. Janes, Michiel Vermeulen, Jitendra Badhai, Maarten van Lohuizen

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Article number100915
JournalCell Reports Medicine
Volume4
Issue number2
DOIs
StatePublished - 21 Feb 2023
Externally publishedYes

Keywords

  • BAP1
  • EZH2
  • Polycomb
  • combination therapy
  • mesothelioma
  • mevalonate
  • preclinical models
  • targeted therapy
  • uveal melanoma

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