دورية أكاديمية
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma
| العنوان: | Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma |
|---|---|
| المؤلفون: | 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 |
| المصدر: | Cell Reports Medicine , Article 100915. (2023) (In press). |
| بيانات النشر: | Elsevier BV |
| سنة النشر: | 2023 |
| المجموعة: | University College London: UCL Discovery |
| مصطلحات موضوعية: | BAP1, EZH2, Polycomb, combination therapy, mesothelioma, mevalonate, preclinical models, targeted therapy, uveal melanoma |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | text |
| اللغة: | English |
| العلاقة: | https://discovery.ucl.ac.uk/id/eprint/10164631/1/1-s2.0-S2666379122004943-main.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10164631Test/ |
| الإتاحة: | https://discovery.ucl.ac.uk/id/eprint/10164631/1/1-s2.0-S2666379122004943-main.pdfTest https://discovery.ucl.ac.uk/id/eprint/10164631Test/ |
| حقوق: | open |
| رقم الانضمام: | edsbas.CD04191E |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |