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dc.contributor.authorSarr, Awa
dc.contributor.authorBré, Jennifer
dc.contributor.authorUm, In Hwa
dc.contributor.authorChan, Tsz Huen
dc.contributor.authorMullen, Peter
dc.contributor.authorHarrison, David J.
dc.contributor.authorReynolds, Paul A.
dc.date.accessioned2019-05-22T09:56:16Z
dc.date.available2019-05-22T09:56:16Z
dc.date.issued2019-05-21
dc.identifier258893627
dc.identifier6899297e-3d19-4bb8-bc84-776966d606f2
dc.identifier85066088455
dc.identifier000468423600015
dc.identifier.citationSarr , A , Bré , J , Um , I H , Chan , T H , Mullen , P , Harrison , D J & Reynolds , P A 2019 , ' Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031 ' , Scientific Reports , vol. 9 , 7643 . https://doi.org/10.1038/s41598-019-44089-3en
dc.identifier.issn2045-2322
dc.identifier.otherORCID: /0000-0001-8738-1245/work/57821645
dc.identifier.otherORCID: /0000-0001-9041-9988/work/64034359
dc.identifier.otherORCID: /0000-0002-0841-609X/work/157141026
dc.identifier.otherORCID: /0000-0001-9999-4292/work/158122917
dc.identifier.urihttps://hdl.handle.net/10023/17738
dc.descriptionA.S. is the recipient of a Medical Research Scotland PhD Studentship awarded to P.A.R. Edinburgh Genomics is partly supported through core grants from Natural Environment Research Council (R8/H10/56), Medical Research Council (MR/K001744/1) and Biotechnological and Biological Research Council (BB/J004243/1). Publication of this article was funded in part by the University of St Andrews Open Access Publishing Fund.en
dc.description.abstractGemcitabine is a fluoropyrimidine analogue that is used as a mainstay of chemotherapy treatment for pancreatic and ovarian cancers, amongst others. Despite its widespread use, gemcitabine achieves responses in less than 10% of patients with metastatic pancreatic cancer and has a very limited impact on overall survival due to intrinsic and acquired resistance. NUC-1031 (Acelarin), a phosphoramidate transformation of gemcitabine, was the first anti-cancer ProTide to enter the clinic. We find it displays important in vitro cytotoxicity differences to gemcitabine, and a genome-wide CRISPR/Cas9 genetic screening approach identified only the pyrimidine metabolism pathway as modifying cancer cell sensitivity to NUC-1031. Low deoxycytidine kinase expression in tumour biopsies from patients treated with gemcitabine, assessed by immunostaining and image analysis, correlates with a poor prognosis, but there is no such correlation in tumour biopsies from a Phase I cohort treated with NUC-1031.
dc.format.extent13
dc.format.extent10164731
dc.language.isoeng
dc.relation.ispartofScientific Reportsen
dc.subjectGemcitabineen
dc.subjectPancreatic canceren
dc.subjectCRISPR–Cas9en
dc.subjectGenome-wide screenen
dc.subjectResistanceen
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectNDASen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.subject.lccRC0254en
dc.titleGenome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031en
dc.typeJournal articleen
dc.contributor.sponsorMedical Research Scotlanden
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.contributor.institutionUniversity of St Andrews. Cellular Medicine Divisionen
dc.contributor.institutionUniversity of St Andrews. Sir James Mackenzie Institute for Early Diagnosisen
dc.contributor.institutionUniversity of St Andrews. Centre for Biophotonicsen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1038/s41598-019-44089-3
dc.description.statusPeer revieweden
dc.identifier.grantnumberen


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