Xu, Duo; Shun-Qing, Liang; Yang, Haitang; Bruggmann, Rémy; Berezowska, Sabina; Zhang, Yang; Marti, Thomas; Hall, Sean Ralph Robert; Gao, Yanyun; Kocher, Gregor J.; Schmid, Ralph A.; Peng, Ren-Wang
(2020).
CRISPR screening identifies WEE1 as a combination target for standard chemotherapy in malignant pleural mesothelioma.
Molecular cancer therapeutics, 19(2), pp. 661-672.
American Association for Cancer Research AACR
10.1158/1535-7163.MCT-19-0724
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Malignant pleural mesothelioma (MPM) is an aggressive cancer with dismal prognosis, largely due to poor response rates to and rapid relapse after first-line pemetrexed (MTA)/cisplatin chemotherapy. A better understanding of the molecular mechanisms underlying chemotherapy sensitivity and duration represents a significant but still unmet clinical need. In this study, we reported on a kinome CRISPR/Cas9 knockout screen that identified several G2-M checkpoint kinases, including WEE1, whose loss of function sensitizes MPM cells to standard chemotherapy. We further showed that deregulation of the G2-M checkpoint contributes to chemotherapy resistance, and that WEE1 inhibition synergizes with cisplatin/MTA, leading to enhanced MPM cell death in vitro and potent anti-tumor effects in vivo. Mechanistically, WEE1 blockage overrides chemotherapy-induced G2-M cell cycle arrest and promotes premature mitotic entry, which causes DNA damage accumulation and ultimately apoptosis. Our results suggest a new therapeutic combination for MPM, and support the application of CRISPR/Cas9-based functional genomics in identifying novel therapeutic targets to potentiate existing cancer therapies.
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Item Type: |
Journal Article
(Original Article)
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery 04 Faculty of Medicine > Faculty Institutions > Teaching Staff, Faculty of Medicine 04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology 04 Faculty of Medicine > Service Sector > Institute of Pathology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Zytometrie-Labor/FACSlab 04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Live Cell Imaging (LCI) 08 Faculty of Science > Department of Biology > Bioinformatics and Computational Biology |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Xu, Duo, Shun-Qing, Liang, Yang, Haitang, Bruggmann, Rémy, Berezowska, Sabina Anna, Yang, Zhang (A), Marti, Thomas, Hall, Sean, Gao, Yanyun, Kocher, Gregor, Schmid, Ralph, Peng, Ren-Wang |
Subjects: |
600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology |
ISSN: |
1535-7163 |
Publisher: |
American Association for Cancer Research AACR |
Language: |
English |
Submitter: |
Thomas Michael Marti
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Date Deposited: |
21 Nov 2019 13:22 |
Last Modified: |
05 Dec 2022 15:32 |
Publisher DOI: |
10.1158/1535-7163.MCT-19-0724 |
PubMed ID: |
31694888 |
URI: |
https://boris.unibe.ch/id/eprint/135013 |
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