Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.

Autor:	Pandey GK; Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Landman N; Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Neikes HK; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Hulsman D; Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands., Lieftink C; Division of Molecular Carcinogenesis, NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Beijersbergen R; Division of Molecular Carcinogenesis, NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Kolluri KK; Lung for Living Research Centre, UCL Respiratory, University College London, Rayne Building, London, UK., Janes SM; Lung for Living Research Centre, UCL Respiratory, University College London, Rayne Building, London, UK., Vermeulen M; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Badhai J; Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. Electronic address: j.badhai@nki.nl., van Lohuizen M; Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. Electronic address: m.v.lohuizen@nki.nl.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2023 Feb 21; Vol. 4 (2), pp. 100915. Date of Electronic Publication: 2023 Jan 18.
DOI:	10.1016/j.xcrm.2022.100915
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu