American Association for Cancer Research
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Supplementary Tables 1-5 from CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma

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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 Table S1. Human kinome sgRNA library used in this study. Supplementary Table S2. PCR primers used in this study. Supplementary Table S3. NGS data of sgRNAs in chemotherapy- and vehicle-treated MESO-1 cells. Supplementary Table S4. Kinase candidates scored in negative selection CRISPR screening. Supplementary Table S5. Sequences of WEE1-specific sgRNAs and negative control sgRNAs.

Funding

Swiss Cancer League

China Scholarship Council

History

ARTICLE ABSTRACT

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.