Chemosensitivity profiling of osteosarcoma tumour cell lines identifies a model of BRCAness.
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Date
2018-07-13ICR Author
Author
Holme, H
Gulati, A
Brough, R
Fleuren, EDG
Bajrami, I
Campbell, J
Chong, IY
Costa-Cabral, S
Elliott, R
Fenton, T
Frankum, J
Jones, SE
Menon, M
Miller, R
Pemberton, HN
Postel-Vinay, S
Rafiq, R
Selfe, JL
von Kriegsheim, A
Munoz, AG
Rodriguez, J
Shipley, J
van der Graaf, WTA
Williamson, CT
Ryan, CJ
Pettitt, S
Ashworth, A
Strauss, SJ
Lord, CJ
Type
Journal Article
Metadata
Show full item recordAbstract
Osteosarcoma (OS) is an aggressive sarcoma, where novel treatment approaches are required. Genomic studies suggest that a subset of OS, including OS tumour cell lines (TCLs), exhibit genomic loss of heterozygosity (LOH) patterns reminiscent of BRCA1 or BRCA2 mutant tumours. This raises the possibility that PARP inhibitors (PARPi), used to treat BRCA1/2 mutant cancers, could be used to target OS. Using high-throughput drug sensitivity screening we generated chemosensitivity profiles for 79 small molecule inhibitors, including three clinical PARPi. Drug screening was performed in 88 tumour cell lines, including 18 OS TCLs. This identified known sensitivity effects in OS TCLs, such as sensitivity to FGFR inhibitors. When compared to BRCA1/2 mutant TCLs, OS TCLs, with the exception of LM7, were PARPi resistant, including those with previously determined BRCAness LoH profiles. Post-screen validation experiments confirmed PARPi sensitivity in LM7 cells as well as a defect in the ability to form nuclear RAD51 foci in response to DNA damage. LM7 provides one OS model for the study of PARPi sensitivity through a potential defect in RAD51-mediated DNA repair. The drug sensitivity dataset we generated in 88 TCLs could also serve as a resource for the study of drug sensitivity effects in OS.
Subject
Cell Line, Tumor
Cell Nucleus
Humans
Osteosarcoma
DNA Damage
BRCA1 Protein
BRCA2 Protein
Drug Screening Assays, Antitumor
DNA Repair
Mutagenesis
Drug Resistance, Neoplasm
Mutation
Rad51 Recombinase
High-Throughput Screening Assays
CRISPR-Cas Systems
Datasets as Topic
Poly(ADP-ribose) Polymerase Inhibitors
Research team
Clinical and Translational Sarcoma
Ashworth Collaborators
Gene Function
Sarcoma Molecular Pathology
Language
eng
Date accepted
2018-07-02
License start date
2018-07-13
Citation
Scientific reports, 2018, 8 (1), pp. 10614 - ?
Publisher
NATURE PUBLISHING GROUP