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

doi:10.1038/s41598-019-44089-3

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 journal › Article › peer-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 language	English
Article number	7643
Number of pages	13
Journal	Scientific Reports
Volume	9
DOIs	https://doi.org/10.1038/s41598-019-44089-3
Publication status	Published - 21 May 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Gemcitabine
Pancreatic cancer
CRISPR–Cas9
Genome-wide screen
Resistance

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Sarr_2019_SR_Genome-scale_CC
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Persistent link to portal record

Investigating resistance mechanisms: Medical Research Scotland - Investigating resistance mechanisms to gemcitabine using gemcitabine analogues and a whole genome RNAi approach
Reynolds, P. (PI)
1/09/14 → 31/08/18
Project: Standard

Paul Reynolds
- par10st-andrews.acuk
Person: Academic

Exploration of the pharmacodynamic profile of Acelarin, a novel ProTide drug, in an in vitro model of ovarian cancer
Bre, J. L. (Author), Harrison, D. J. (Supervisor), 28 Jun 2019
Student thesis: Doctoral Thesis (PhD)

Cite this

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title = "Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031",

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.",

keywords = "Gemcitabine, Pancreatic cancer, CRISPR{\textendash}Cas9, Genome-wide screen, Resistance",

author = "Awa Sarr and Jennifer Br{\'e} and Um, \{In Hwa\} and Chan, \{Tsz Huen\} and Peter Mullen and Harrison, \{David J.\} and Reynolds, \{Paul A.\}",

note = "A.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.",

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doi = "10.1038/s41598-019-44089-3",

language = "English",

volume = "9",

journal = "Scientific Reports",

issn = "2045-2322",

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T1 - Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031

AU - Sarr, Awa

AU - Bré, Jennifer

AU - Um, In Hwa

AU - Chan, Tsz Huen

AU - Mullen, Peter

AU - Harrison, David J.

AU - Reynolds, Paul A.

N1 - A.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.

PY - 2019/5/21

Y1 - 2019/5/21

N2 - 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.

AB - 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.

KW - Gemcitabine

KW - Pancreatic cancer

KW - CRISPR–Cas9

KW - Genome-wide screen

KW - Resistance

U2 - 10.1038/s41598-019-44089-3

DO - 10.1038/s41598-019-44089-3

M3 - Article

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

M1 - 7643

ER -

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

Abstract

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Keywords

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Projects

Investigating resistance mechanisms: Medical Research Scotland - Investigating resistance mechanisms to gemcitabine using gemcitabine analogues and a whole genome RNAi approach

Profiles

Paul Reynolds

Student theses

Exploration of the pharmacodynamic profile of Acelarin, a novel ProTide drug, in an in vitro model of ovarian cancer

Cite this