American Association for Cancer Research
15357163mct190724-sup-226033_3_supp_5850210_pzs0py.pdf (224.22 kB)

Figure S1 from CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma

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journal contribution
posted on 2023-04-03, 18:26 authored by Duo Xu, Shun-Qing Liang, Haitang Yang, Rémy Bruggmann, Sabina Berezowska, Zhang Yang, Thomas Michael Marti, Sean Ralph Robert Hall, Yanyun Gao, Gregor J. Kocher, Ralph A. Schmid, Ren-Wang Peng

Supplementary Figure S1. Genes regulating the G2-M cell cycle transition are deregulated in MPM.


Swiss Cancer League

China Scholarship Council



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 antitumor 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.