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Dissecting PARP inhibitor resistance with functional genomics.

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Date
2019-02
ICR Author
Lord, Christopher
Pettitt, Stephen
Author
Pettitt, SJ
Lord, CJ
Type
Journal Article
Metadata
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Abstract
The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. Multiple different PARPi have now been approved for use in a wider group of gynaecological cancers as well as for the treatment of BRCA-gene mutant breast cancer. Despite these advances, resistance to PARPi is a common clinical phenotype. Understanding, at the molecular level, how tumour cells respond to PARPi has the potential to inform how these drugs should be used clinically and since the discovery of this drug class, multiple different functional genomic strategies have been employed to dissect PARPi sensitivity and resistance. These have included genetic perturbation via classical gene targeting, gene silencing by siRNA or shRNA or transposon mutagenesis techniques. Recently, CRISPR-Cas9-based mutagenesis has greatly expanded the available range of relevant preclinical models and the precision of mutagenesis. Here, we review how these approaches have been used either in low-throughput, hypothesis-testing experiments or in the setting of large, hypothesis-generating, genetic screens aimed at understanding the molecular basis of PARPi sensitivity and resistance.
URI
https://repository.icr.ac.uk/handle/internal/3250
DOI
https://doi.org/10.1016/j.gde.2019.03.001
Collections
  • Breast Cancer Research
  • Molecular Pathology
Subject
Humans
Breast Neoplasms
Ovarian Neoplasms
Piperazines
Phthalazines
Poly(ADP-ribose) Polymerases
BRCA1 Protein
BRCA2 Protein
Drug Resistance, Neoplasm
Germ-Line Mutation
Female
Poly(ADP-ribose) Polymerase Inhibitors
Research team
Gene Function
Language
eng
Date accepted
2019-03-02
License start date
2019-02
Citation
Current opinion in genetics & development, 2019, 54 pp. 55 - 63

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