Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma

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, w...

Full description

Saved in:
Bibliographic Details
Published in:Cell reports. Medicine Vol. 4; no. 2; p. 100915
Main Authors: Pandey, Gaurav Kumar, Landman, Nick, Neikes, Hannah K., Hulsman, Danielle, Lieftink, Cor, Beijersbergen, Roderick, Kolluri, Krishna Kalyan, Janes, Sam M., Vermeulen, Michiel, Badhai, Jitendra, van Lohuizen, Maarten
Format: Journal Article
Language:English
Published: United States Elsevier Inc 21.02.2023
Elsevier
Subjects:
Advanced Basic Science
Animals
BAP1
Cholesterol
combination therapy
EZH2
Humans
Lung Neoplasms - genetics
mesothelioma
Mesothelioma - genetics
Mesothelioma - pathology
Mesothelioma, Malignant
mevalonate
Mevalonic Acid
Mice
Polycomb
preclinical models
targeted therapy
Tumor Suppressor Proteins - genetics
Ubiquitin Thiolesterase - genetics
Ubiquitin Thiolesterase - metabolism
uveal melanoma
targeted therapy
preclinical models
uveal melanoma
Polycomb
combination therapy
mesothelioma
mevalonate
BAP1
EZH2
ISSN:2666-3791, 2666-3791
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] •CRISPR-Cas9 kinome screen identifies new dependencies in BAP1-deficient mesothelioma•Mesothelioma cells lacking BAP1 are vulnerable to mevalonate pathway inhibition•Mevalonate pathway combined with EZH2 inhibition is potent against BAP1-mutated tumors•This combination is well tolerated and prolongs survival in in vivo mesothelioma models BAP1 mutant mesothelioma tumors have a poor prognosis and few therapeutic options. Here, Pandey and Landman et al. show that the combined targeting of mevalonate pathway and EZH2 inhibition effectively kills tumor cells and prolongs the survival of Bap1-deficient mice with mesothelioma.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Present address: Department of Zoology, Banaras Hindu University, Varanasi 221005, India
These authors contributed equally
Senior author
Lead contact
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2022.100915