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Novel splice‐switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action
Author(s) -
Smith Lindsay D.,
Leme de Calais Flávia,
Raponi Michela,
Mellone Massimiliano,
Buratti Emanuele,
Blaydes Jeremy P.,
Baralle Diana
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30574
Subject(s) - rna splicing , parp inhibitor , splice , action (physics) , oligonucleotide , cancer research , genetics , biology , computational biology , poly adp ribose polymerase , medicine , dna , physics , gene , rna , polymerase , quantum mechanics
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.