CRISPR screening identifies WEE1 as a combination target for standard chemotherapy in malignant pleural mesothelioma.

Xu, Duo; Liang, Shun-Qing; Yang, Haitang; Bruggmann, Rémy; Berezowska, Sabina; Zhang, Yang; Marti, Thomas Michael; 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
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)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Xu, Duo; Yang, Haitang; Bruggmann, Rémy; Berezowska, Sabina Anna; Zhang, Yang; Marti, Thomas; Hall, Sean; Gao, Yanyun; Kocher, Gregor; Schmid, Ralph and Peng, Ren-Wang

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1535-7163

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

21 Nov 2019 13:22

Last Modified:

09 Feb 2020 01:31

Publisher DOI:

10.1158/1535-7163.MCT-19-0724

PubMed ID:

31694888

URI:

https://boris.unibe.ch/id/eprint/135013

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