Identification of therapeutic targets and dependencies in ZNF703-amplified breast cancer

Focal amplifications of the chromosome 8p11.23, likely precipitated by oestrogen-induced chromosomal instability, are recurrent in 15% of breast cancer, defines the IntClust6 subtype, and portends poor prognosis with high risk of late relapse and chemotherapy resistance. ZNF703 is the most frequently amplified gene and the putative driver oncogene within this locus, though mechanisms are poorly understood. To identify therapeutic vulnerabilities for ZNF703-amplified breast cancers, wholegenome CRISPR-Cas9 screens were performed in isogenic cell lines with modulated ZNF703 expression alongside ZNF703-amplified cells. Here we report that ZNF703 amplification is synthetic lethal with loss of OTUD5, a regulator of DNA double strand break repair and interferon signalling. Furthermore, ZNF703 overexpression favours error-free repair of CRISPR-Cas9-induced double strand breaks and confers increased dependency on homologous recombination. Interactomic and transcriptomic profiling suggests ZNF703 binds to transcriptional repressors and interferon-related transcription factors, resulting in downregulation of interferon response. Notably, underexpression of interferon response genes is associated with dependency on OTUD5 and BRCA1. Together, these findings propose that ZNF703 facilitates cell growth under chromosomal instability, and antagonism of this function by OTUD5 loss represents a promising therapeutic strategy.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Lui, Allan

Advisors dc:contributor.advisor

• Brenton, James
• Caldas, Carlos

• Cancer

Licence

• https://www.repository.cam.ac.uk/bitstreams/0b2007e9-673d-4c8c-aa36-94b17998a642/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

Author Identifier

0000-0001-7624-3437

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/393117