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...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Cell reports. Medicine Ročník 4; číslo 2; s. 100915
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 21.02.2023 Elsevier
Témata:	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
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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.
Bibliografie:	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