ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
24 11 2023
24 11 2023
Historique:
medline:
27
11
2023
pubmed:
22
11
2023
entrez:
22
11
2023
Statut:
ppublish
Résumé
Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer.
Identifiants
pubmed: 37992168
doi: 10.1126/sciadv.adg2263
pmc: PMC10664985
doi:
Substances chimiques
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Antineoplastic Agents
0
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
ATM protein, human
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eadg2263Subventions
Organisme : NCI NIH HHS
ID : U01 CA260369
Pays : United States
Organisme : NCI NIH HHS
ID : C06 CA059267
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA228696
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA272657
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA259007
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
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