Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors.

Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors Humans Male Neoplasm Staging Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use Prostatic Neoplasms / drug therapy Retrospective Studies Tumor Cells, Cultured

ATM ATR inhibition DNA damage response PARP inhibition Prostate cancer Synthetic lethality

Journal

European urology

ISSN: 1873-7560

Titre abrégé: Eur Urol

Pays: Switzerland

ID NLM: 7512719

Informations de publication

Date de publication:
02 2021

Historique:

received: 22 05 2020

accepted: 18 10 2020

pubmed: 13 11 2020

medline: 18 9 2021

entrez: 12 11 2020

Statut: ppublish

Résumé

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. To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset. 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. 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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.eururo.2020.10.029 PMID: 33176972

pubmed: 33176972

pii: S0302-2838(20)30836-8

doi: 10.1016/j.eururo.2020.10.029

pii:

doi:

Substances chimiques

Poly(ADP-ribose) Polymerase Inhibitors 0

ATM protein, human EC 2.7.11.1

ATR protein, human EC 2.7.11.1

Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

Pagination

200-211

Subventions

Organisme : Medical Research Council

ID : MC_U120085810

Pays : United Kingdom

Organisme : Cancer Research UK

Pays : United Kingdom

Organisme : Department of Health [UK]

Commentaires et corrections

Type : CommentIn