BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance

K Nesic; JJ Krais; Y Wang; CJ Vandenberg; P Patel; KQ Cai; T Kwan; E Lieschke; GY Ho; HE Barker; J Bedo; S Casadei; A Farrell; M Radke; K Shield-Artin; JS Penington; F Geissler; E Kyran; R Betsch; L Xu; F Zhang; A Dobrovic; I Olesen; R Kristeleit; A Oza; I McNeish; G Ratnayake; N Traficante; N Zeps; D Whiteman; D Purdie; I Haviv; M Buck; A McCartney; Y Leung; I Hammond; V Ganju; R Blum; LF Ng; R Bell; C Underhill; M Quinn; D Neesham; J Pyman; V Billson; P Waring; W Murray; N O’Callaghan; M Loughrey; S Lade; D Johnson; S Fox; D Rischin; K Phillips; I Simpson; E Sumithran; B Susil; P Rogers; J McNealage; T Manolitsas; T Jobling; D Healy; M Robbie; R Laurie; S Hyde; P Grant; D Allen; R Rome; B Brown; A Parker; R McIntosh; D Challis; P Blomfield; J Pierdes; J Miller; D Henderson; K Pittman; T Healy; T Dodd; C Hall; MK Oehler; M Davy; J Nicklin; D Wyld; L Perrin; A Obermair; K Horwood; M Cummings; A Crandon; D Papadimos; B Ward; G Wain; R Sharma; P Harnett; R Jaworski; K Byth; A Brand; J Hill; J Grygiel; M Links

Journal article

BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance

K Nesic, JJ Krais, Y Wang, CJ Vandenberg, P Patel, KQ Cai, T Kwan, E Lieschke, GY Ho, HE Barker, J Bedo, S Casadei, A Farrell, M Radke, K Shield-Artin, JS Penington, F Geissler, E Kyran, R Betsch, L Xu Show all

Molecular Cancer | Published : 2024

DOI: 10.1186/s12943-024-02048-1

Abstract

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood. We analyzed nine ovarian and breast cancer patient derived xenografts ..

View full abstract

University of Melbourne Researchers

Ksenija Nesic Author

Cassandra Vandenberg Author

Holly Barker Author

Justin Bedo Author

Related Projects (3)

Molecular Epidemiology of Ovarian Research Institute

PUBLIC ABSTRACT A major obstacle to preventive strategies for ovarian cancer is the lack of recognized modifiable risk factors. Age, a pos..

Molecular Epidemiology of Ovarian Cancer: The Australian Ovarian Cancer Study National Clinical Follow-Up Core

Ovarian cancer is the seventh most common cancer in Australian women and fifth most common cause of cancer death, with approximately 1200 ne..

AUSTRALIAN OVARIAN CANCER STUDY (AOCS): A MULTIDISCIPLINARY OVARIAN CANCER RESOURCE FOR THE GENOMICS ERA

Ovarian cancer is relatively uncommon and is histologically very diverse, making it difficult to analyse ovarian cancer at a molecular level..

Grants

Awarded by National Health and Medical Research Council

Funding Acknowledgements

We thank Silvia Stoev, Rachel Hancock, Kathy Barber, Scott Wood and Conrad Leonard for technical assistance. We thank Amanda Spurdle and Michael Parsons (QIMR Berghofer) for their advice regarding BRCA1 SNPs potentially affecting splicing. We thank Clovis Oncology for providing rucaparib for in vivo experiments; Violeta Serra and Judith Balmana for the PDX models #124 and #196; Elgene Lim for #1126, Scott H. Kaufmann for PEO1 and PEO4 cell lines and Dale Garsed and David Bowtell for the UWB1.289 cell line.