Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors

Background: 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. Objective: 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 inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models. Conclusions: ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition. Patient summary: Of aggressive prostate cancers, 10% lose the DNA repair gene ATM; this loss may identify a distinct prostate cancer subtype that is most sensitive to oral drugs targeting both PARP and ATR. (C) 2020 The Authors. Published by Elsevier B.V.

Automated summary

Deleterious ATM alterations are present in 10% of prostate cancer cases, and this subset is most sensitive to a combination of PARP and ATR inhibitors. In vitro studies show that ATM-deficient prostate cancer models respond well to ATR inhibition, with variable sensitivity to PARP inhibition, but superior antitumour activity is observed with combined PARP and ATR inhibition.