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The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin

Wang, Yifan; Bernhardy, Andrea J.; Cruz, Cristina; Krais, John J.; Nacson, Joseph; Nicolas, Emmanuelle; Peri, Suraj; Van Der Gulden, Hanneke; Van Der Heijden, Ingrid and O'Brien, Shane W., et al. (2016) In Cancer Research 76(9). p.2778-2790
Abstract

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and... (More)

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1- Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance.

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@misc{1e41ee44-78fb-42f7-b265-ff2174920ec2,
  abstract     = {<p>Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1- Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance.</p>},
  author       = {Wang, Yifan and Bernhardy, Andrea J. and Cruz, Cristina and Krais, John J. and Nacson, Joseph and Nicolas, Emmanuelle and Peri, Suraj and Van Der Gulden, Hanneke and Van Der Heijden, Ingrid and O'Brien, Shane W. and Zhang, Yong and Harrell, Maribel I. and Johnson, Shawn F. and Candido Dos Reis, Francisco J. and Pharoah, Paul D P and Karlan, Beth and Gourley, Charlie and Lambrechts, Diether and Chenevix-Trench, Georgia and Olsson, Håkan and Benitez, Javier J. and Greene, Mark H. and Gore, Martin and Nussbaum, Robert and Sadetzki, Siegal and Gayther, Simon A. and Kjaer, Susanne K. and K'Con Fab, Fab and D'Andrea, Alan D. and Shapiro, Geoffrey I. and Wiest, David L. and Connolly, Denise C. and Daly, Mary B. and Swisher, Elizabeth M. and Bouwman, Peter and Jonkers, Jos and Balmaña, Judith and Serra, Violeta and Johnson, Neil},
  issn         = {0008-5472},
  language     = {eng},
  number       = {9},
  pages        = {2778--2790},
  publisher    = {ARRAY(0xb9d0218)},
  series       = {Cancer Research},
  title        = {The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-16-0186},
  volume       = {76},
  year         = {2016},
}