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Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031

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Abstract

Gemcitabine 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.
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Original languageEnglish
Article number7643
Number of pages13
JournalScientific Reports
Volume9
DOIs
Publication statusPublished - 21 May 2019

    Research areas

  • Gemcitabine, Pancreatic cancer, CRISPR–Cas9, Genome-wide screen, Resistance

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