Key result
RNA splice-switching oligonucleotide targeting BRCA1 exon 11 sensitizes wild-type cells to PARP inhibitors.
Why the study?
Breast cancer tumors with nonmutated functional BRCA1 are less sensitive to PARP inhibition, necessitating methods to induce susceptibility in these tumors.
Does an RNA splice-switching oligonucleotide targeting BRCA1 exon 11 increase susceptibility to PARP inhibitors in wild-type BRCA1 expressing breast cancer cells?
Does an RNA splice-switching oligonucleotide targeting BRCA1 exon 11 increase susceptibility to PARP inhibitors in wild-type BRCA1 expressing breast cancer cells?
An RNA splice-switching oligonucleotide targeting BRCA1 exon 11 can artificially induce exon skipping, rendering BRCA1-functional breast cancer cells susceptible to PARP inhibitors.
Could broaden PARP inhibitor use to BRCA1-proficient tumors; leaves open clinical translation.
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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Smith et al. (2016) studied BRCA1-functional breast cancer. Splice-switching oligonucleotide (SSO) targeting BRCA1 exon 11 was evaluated on Cell survival and γH2AX expression. An RNA splice-switching oligonucleotide targeting BRCA1 exon 11 rendered wild-type BRCA1 expressing cell lines more susceptible to PARP inhibitor treatment by reducing cell survival.
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