Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma.

ABSTRACT:

Background

In neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research.

Methods

To evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Cas9 gene editing to generate neuroblastoma cell lines isogenic for ATRX. We used these and other models to identify therapeutically exploitable synthetic lethal vulnerabilities associated with ATRX LoF.

Findings

In isogenic cell lines, we found that ATRX inactivation results in increased DNA damage, homologous recombination repair (HRR) defects and impaired replication fork processivity. In keeping with this, high-throughput compound screening showed selec

SUBMITTER: George SL 

PROVIDER: S-EPMC7452577 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature