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    A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors

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    Author
    Qiu, Zhaojun
    Fa, Pengyan
    Liu, Tao
    Prasad, Chandra B
    Ma, Shanhuai
    Hong, Zhipeng
    Chan, Ernest R
    Wang, Hongbing
    Li, Zaibo
    He, Kai
    Wang, Qi-En
    Williams, Terence M
    Yan, Chunhong
    Sizemore, Steven T
    Narla, Goutham
    Zhang, Junran
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    Date
    2020-06-10
    Journal
    Cancer Research
    Publisher
    American Association for Cancer Research
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1158/0008-5472.CAN-20-0057
    Abstract
    There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non-small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition. A synthetic lethal interaction between PPP2R2A deficiency and ATR or CHK1 inhibition was observed in NSCLC in vitro and in vivo and was independent of p53 status. ATR and CHK1 inhibition resulted in significantly increased levels of RS and altered replication dynamics, particularly in PPP2R2A-deficient NSCLC cells. Mechanistically, PPP2R2A negatively regulated translation of oncogene c-Myc protein. c-Myc activity was required for PPP2R2A deficiency-induced alterations of replication initiation/RS and sensitivity to ATR/CHK1 inhibitors. We conclude that PPP2R2A deficiency elevates RS by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Our studies show a novel synthetic lethal interaction and identify PPP2R2A as a potential new predictive biomarker for patient stratification in the clinical use of ATR and CHK1 inhibitors. SIGNIFICANCE: This study reveals new approaches to specifically target PPP2R2A-deficient lung cancer cells and provides a novel biomarker that will significantly improve treatment outcome with ATR and CHK1 inhibitors.
    Keyword
    replication stress
    Biomarkers
    Carcinoma, Non-Small-Cell Lung
    Genome-Wide Association Study
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13604
    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-20-0057
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