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

Awa Sarr, Jennifer Bré, In Hwa Um, Tsz Huen Chan, Peter Mullen, David J Harrison, Paul A Reynolds

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article number7643
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 21 May 2019

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