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dc.contributor.authorQiu, Zhaojun
dc.contributor.authorFa, Pengyan
dc.contributor.authorLiu, Tao
dc.contributor.authorPrasad, Chandra B
dc.contributor.authorMa, Shanhuai
dc.contributor.authorHong, Zhipeng
dc.contributor.authorChan, Ernest R
dc.contributor.authorWang, Hongbing
dc.contributor.authorLi, Zaibo
dc.contributor.authorHe, Kai
dc.contributor.authorWang, Qi-En
dc.contributor.authorWilliams, Terence M
dc.contributor.authorYan, Chunhong
dc.contributor.authorSizemore, Steven T
dc.contributor.authorNarla, Goutham
dc.contributor.authorZhang, Junran
dc.date.accessioned2020-09-01T14:52:05Z
dc.date.available2020-09-01T14:52:05Z
dc.date.issued2020-06-10
dc.identifier.urihttp://hdl.handle.net/10713/13604
dc.description.abstractThere 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.en_US
dc.description.urihttps://doi.org/10.1158/0008-5472.CAN-20-0057en_US
dc.language.isoen_USen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.relation.ispartofCancer Researchen_US
dc.subjectreplication stressen_US
dc.subject.meshBiomarkersen_US
dc.subject.meshCarcinoma, Non-Small-Cell Lungen_US
dc.subject.meshGenome-Wide Association Studyen_US
dc.titleA Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitorsen_US
dc.typeArticleen_US
dc.identifier.doi10.1158/0008-5472.CAN-20-0057
dc.identifier.pmid32522823
dc.source.volume80
dc.source.issue16
dc.source.beginpage3305
dc.source.endpage3318
dc.source.countryUnited States


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