CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma

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 re...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2020-02, Vol.19 (2), p.661-672
Main Authors: Xu, Duo, Liang, Shun-Qing, Yang, Haitang, Bruggmann, Rémy, Berezowska, Sabina, Yang, Zhang, Marti, Thomas Michael, Hall, Sean Ralph Robert, Gao, Yanyun, Kocher, Gregor J, Schmid, Ralph A, Peng, Ren-Wang
Format: Article
Language:English
Subjects:
Aged
Animals
Cell Cycle Proteins - antagonists & inhibitors
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Clustered Regularly Interspaced Short Palindromic Repeats
Humans
Male
Mesothelioma, Malignant - drug therapy
Mesothelioma, Malignant - genetics
Mice
Molecular Targeted Therapy
Pleural Neoplasms - drug therapy
Pleural Neoplasms - genetics
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
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Summary: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 G -M checkpoint kinases, including WEE1, whose loss of function sensitizes MPM cells to standard chemotherapy. We further showed that deregulation of the G -M checkpoint contributes to chemotherapy resistance, and that WEE1 inhibition synergizes with cisplatin/MTA, leading to enhanced MPM cell death and potent antitumor effects Mechanistically, WEE1 blockage overrides chemotherapy-induced G -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.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.mct-19-0724