Pandey, Gaurav Kumar;
Landman, Nick;
Neikes, Hannah K;
Hulsman, Danielle;
Lieftink, Cor;
Beijersbergen, Roderick;
Kolluri, Krishna Kalyan;
... van Lohuizen, Maarten; + view all
(2023)
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.
Cell Reports Medicine
, Article 100915. 10.1016/j.xcrm.2022.100915.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.xcrm.2022.100915 |
| Publisher version: | https://doi.org/10.1016/j.xcrm.2022.100915 |
| Language: | English |
| Additional information: | © 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | BAP1, EZH2, Polycomb, combination therapy, mesothelioma, mevalonate, preclinical models, targeted therapy, uveal melanoma |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10164631 |
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