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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Yifan Wang
  • Andrea J. Bernhardy
  • Cristina Cruz
  • John J. Krais
  • Joseph Nacson
  • Emmanuelle Nicolas
  • Suraj Peri
  • Hanneke Van Der Gulden
  • Ingrid Van Der Heijden
  • Shane W. O'Brien
  • Yong Zhang
  • Maribel I. Harrell
  • Shawn F. Johnson
  • Francisco J. Candido Dos Reis
  • Paul D P Pharoah
  • Beth Karlan
  • Charlie Gourley
  • Diether Lambrechts
  • Georgia Chenevix-Trench
  • Javier J. Benitez
  • Mark H. Greene
  • Martin Gore
  • Robert Nussbaum
  • Siegal Sadetzki
  • Simon A. Gayther
  • Susanne K. Kjaer
  • Fab K'Con Fab
  • Alan D. D'Andrea
  • Geoffrey I. Shapiro
  • David L. Wiest
  • Denise C. Connolly
  • Mary B. Daly
  • Elizabeth M. Swisher
  • Peter Bouwman
  • Jos Jonkers
  • Judith Balmaña
  • Violeta Serra
  • Neil Johnson
Organisations
External organisations
  • Fox Chase Cancer Center
  • Netherlands Cancer Institute
  • Vall d'Hebron University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)2778-2790
Number of pages13
JournalCancer Research
Volume76
Issue number9
Publication statusPublished - 2016
Publication categoryResearch
Peer-reviewedYes