Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma.
Animals
Antigens, Surface
/ genetics
Ataxia Telangiectasia Mutated Proteins
/ genetics
Cell Cycle Proteins
/ genetics
Cyclin-Dependent Kinases
/ genetics
Drug Resistance, Neoplasm
Female
Glioblastoma
/ drug therapy
Homologous Recombination
Humans
Mice
Mice, SCID
N-Myc Proto-Oncogene Protein
/ genetics
Neoplastic Stem Cells
/ metabolism
Poly (ADP-Ribose) Polymerase-1
/ genetics
Poly(ADP-ribose) Polymerase Inhibitors
/ administration & dosage
Protein Binding
Proto-Oncogene Proteins c-myc
/ genetics
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 07 2019
02 07 2019
Historique:
received:
22
10
2018
accepted:
13
06
2019
entrez:
4
7
2019
pubmed:
4
7
2019
medline:
10
9
2019
Statut:
epublish
Résumé
PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.
Identifiants
pubmed: 31266951
doi: 10.1038/s41467-019-10993-5
pii: 10.1038/s41467-019-10993-5
pmc: PMC6606647
doi:
Substances chimiques
Antigens, Surface
0
Cell Cycle Proteins
0
ETAA1 protein, human
0
MYC protein, human
0
MYCN protein, human
0
N-Myc Proto-Oncogene Protein
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Proto-Oncogene Proteins c-myc
0
rad9 protein
139691-42-2
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Cyclin-Dependent Kinases
EC 2.7.11.22
PCTAIRE-3 protein kinase
EC 2.7.11.22
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
2910Subventions
Organisme : NCI NIH HHS
ID : R01 CA160762
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS032677
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA160762
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : R01NS032677
Pays : International
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