Therapeutic targeting of ATR in alveolar rhabdomyosarcoma.
Ataxia Telangiectasia Mutated Proteins
/ genetics
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Oncogene Proteins, Fusion
/ genetics
PAX3 Transcription Factor
/ genetics
Paired Box Transcription Factors
/ genetics
Rhabdomyosarcoma
/ genetics
Rhabdomyosarcoma, Alveolar
/ drug therapy
Rhabdomyosarcoma, Embryonal
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 07 2022
25 07 2022
Historique:
received:
20
12
2020
accepted:
11
07
2022
entrez:
25
7
2022
pubmed:
26
7
2022
medline:
28
7
2022
Statut:
epublish
Résumé
Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.
Identifiants
pubmed: 35879366
doi: 10.1038/s41467-022-32023-7
pii: 10.1038/s41467-022-32023-7
pmc: PMC9314382
doi:
Substances chimiques
Oncogene Proteins, Fusion
0
PAX3 Transcription Factor
0
Paired Box Transcription Factors
0
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4297Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
© 2022. The Author(s).
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