Related Experiment Video
Updated: Nov 30, 2025
A New Technique for Treating Low-risk Prostate Cancer—Super Active Surveillance
Published on: November 7, 2025
Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors
Antje Neeb1, Nicolás Herranz2, Sara Arce-Gallego2
1The Institute of Cancer Research, London, UK.
Background:
Deleterious ATM alterations are found in metastatic prostate cancer (PC); 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. 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.
Outcome Measurements And Statistical Analysis:
ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models.
Results And Limitations:
Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss 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 (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, 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 the combination of oral drugs targeting PARP and ATR.
Insights
Deleterious ATM alterations in metastatic prostate cancer (PC) are linked to genomic instability. ATM-deficient PC models show sensitivity to combined ATR and PARP inhibition, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Deleterious ATM alterations occur in metastatic prostate cancer (PC).
- PARP inhibition shows antitumor activity in some ATM-loss PCs, but response is variable.
- Understanding ATM deficiency is crucial for targeted therapies.
Purpose of the Study:
- Characterize ATM-deficient lethal PC.
- Investigate synthetic lethal therapeutic strategies for ATM-deficient PC.
- Identify optimal drug combinations for this PC subset.
Main Methods:
- Studied advanced PC biopsies using immunohistochemistry (IHC) and next-generation sequencing (NGS).
- Generated and utilized CRISPR-Cas9 modified cell line models for drug sensitivity assays.
- Validated findings in patient-derived models.
Main Results:
- ATM IHC loss detected in 11% of PC patients, with intrapatient heterogeneity.
- ATM loss associated with increased genomic instability (NtAI, large-scale transitions).
- ATM-loss PC models sensitive to ATR inhibition, variably to PARP inhibition; superior activity with combined ATR and PARP inhibition.
Conclusions:
- ATM loss in PC is not always detected by NGS and associates with genomic instability.
- ATM-deficient PC is most sensitive to combined ATR and PARP inhibition.
- This combination therapy may represent a novel strategy for a distinct PC subtype.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:37DNA Damage can Stall the Cell Cycle
02:56Treatment Resistant Cancers