Deleterious ATM alterations are found in prostate cancer (PC) and associate with a higher grade; PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond.
To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset.
Design, setting, and participants
We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays.
Outcome measurements and statistical analysis
In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model.
Results and limitations
Overall, we detected ATM IHC loss in 68/631 (11%) PC patients with synchronous and metachronous intrapatient heterogeneity; 45/61 (74%) of ATM loss tumours had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (the number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transition, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP.