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Novel splice-switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action

Novel splice-switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action
Novel splice-switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action
Tumors carrying hereditary mutations in BRCA1, which attenuate the BRCA1 DNA damage repair pathway, are more susceptible to dual treatment with PARP inhibitors and DNA damaging therapeutics. Conversely, breast cancer tumors with nonmutated functional BRCA1 are less sensitive to PARP inhibition. We describe a method that triggers susceptibility to PARP inhibition in BRCA1‐functional tumor cells. BRCA1 exon 11 is a key for the function of BRCA1 in DNA damage repair. Analysis of the BRCA1 exon 11 splicing mechanism identified a key region within this exon which, when deleted, induced exon 11 skipping. An RNA splice‐switching oligonucleotide (SSO) developed to target this region was shown to artificially stimulate skipping of exon 11 in endogenous BRCA1 pre‐mRNA. SSO transfection rendered wild‐type BRCA1 expressing cell lines more susceptible to PARP inhibitor treatment, as demonstrated by a reduction in cell survival at all SSO concentrations tested. Combined SSO and PARP inhibitor treatment increased γH2AX expression indicating that SSO‐dependent skipping of BRCA1 exon 11 was able to promote DSBs and therefore synthetic lethality. In conclusion, this SSO provides a new potential therapeutic strategy for targeting BRCA1‐functional breast cancer by enhancing the effect of PARP inhibitors.
0020-7136
1564-1570
Smith, Lindsay
1d44c2d0-d5af-411e-b6cd-9b5633f2eb1e
Leme De Calais, Flavia
d648d35b-dc15-426d-b62c-5e2367248bd9
Raponi, Michela
f465e77f-b9bf-4c32-80d6-43c0787542b9
Mellone, Massimiliano
b0301b32-14f8-4203-9026-b7f90885cab9
Buratti, Emanuele
57e8e002-a8c2-409a-ac29-2fc4a1d1c8b9
Blaydes, Jeremy
e957f999-fd91-4f77-ad62-5b4ef069b15b
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Smith, Lindsay
1d44c2d0-d5af-411e-b6cd-9b5633f2eb1e
Leme De Calais, Flavia
d648d35b-dc15-426d-b62c-5e2367248bd9
Raponi, Michela
f465e77f-b9bf-4c32-80d6-43c0787542b9
Mellone, Massimiliano
b0301b32-14f8-4203-9026-b7f90885cab9
Buratti, Emanuele
57e8e002-a8c2-409a-ac29-2fc4a1d1c8b9
Blaydes, Jeremy
e957f999-fd91-4f77-ad62-5b4ef069b15b
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91

Smith, Lindsay, Leme De Calais, Flavia, Raponi, Michela, Mellone, Massimiliano, Buratti, Emanuele, Blaydes, Jeremy and Baralle, Diana (2017) Novel splice-switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action. International Journal of Cancer, 140 (7), 1564-1570. (doi:10.1002/ijc.30574). (PMID:27997688)

Record type: Article

Abstract

Tumors carrying hereditary mutations in BRCA1, which attenuate the BRCA1 DNA damage repair pathway, are more susceptible to dual treatment with PARP inhibitors and DNA damaging therapeutics. Conversely, breast cancer tumors with nonmutated functional BRCA1 are less sensitive to PARP inhibition. We describe a method that triggers susceptibility to PARP inhibition in BRCA1‐functional tumor cells. BRCA1 exon 11 is a key for the function of BRCA1 in DNA damage repair. Analysis of the BRCA1 exon 11 splicing mechanism identified a key region within this exon which, when deleted, induced exon 11 skipping. An RNA splice‐switching oligonucleotide (SSO) developed to target this region was shown to artificially stimulate skipping of exon 11 in endogenous BRCA1 pre‐mRNA. SSO transfection rendered wild‐type BRCA1 expressing cell lines more susceptible to PARP inhibitor treatment, as demonstrated by a reduction in cell survival at all SSO concentrations tested. Combined SSO and PARP inhibitor treatment increased γH2AX expression indicating that SSO‐dependent skipping of BRCA1 exon 11 was able to promote DSBs and therefore synthetic lethality. In conclusion, this SSO provides a new potential therapeutic strategy for targeting BRCA1‐functional breast cancer by enhancing the effect of PARP inhibitors.

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Accepted/In Press date: 5 December 2016
e-pub ahead of print date: 20 December 2016
Published date: April 2017
Organisations: Cancer Sciences, Human Development & Health

Identifiers

Local EPrints ID: 403762
URI: http://eprints.soton.ac.uk/id/eprint/403762
ISSN: 0020-7136
PURE UUID: 373d5ef9-cf54-42e6-bb8a-7528a67bac68
ORCID for Massimiliano Mellone: ORCID iD orcid.org/0000-0002-4964-9340
ORCID for Jeremy Blaydes: ORCID iD orcid.org/0000-0001-8525-0209
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 09 Dec 2016 16:33
Last modified: 22 Nov 2021 02:59

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Contributors

Author: Lindsay Smith
Author: Flavia Leme De Calais
Author: Michela Raponi
Author: Massimiliano Mellone ORCID iD
Author: Emanuele Buratti
Author: Jeremy Blaydes ORCID iD
Author: Diana Baralle ORCID iD

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