TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment.
PARP inhibitor resistance
TGFβR signaling
bone marrow microenvironment
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
06 10 2020
06 10 2020
Historique:
received:
08
04
2020
revised:
18
08
2020
accepted:
10
09
2020
entrez:
7
10
2020
pubmed:
8
10
2020
medline:
16
9
2021
Statut:
ppublish
Résumé
Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFβR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-β1). Genetic and/or pharmacological targeting of the TGF-β1-TGFβR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFβR inhibitor in patients receiving PARPis.
Identifiants
pubmed: 33027668
pii: S2211-1247(20)31210-9
doi: 10.1016/j.celrep.2020.108221
pmc: PMC7578922
mid: NIHMS1635590
pii:
doi:
Substances chimiques
Poly(ADP-ribose) Polymerase Inhibitors
0
Receptors, Transforming Growth Factor beta
0
SMAD3 protein, human
0
Smad3 Protein
0
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
108221Subventions
Organisme : NCI NIH HHS
ID : UG1 CA233290
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220499
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247707
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233332
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244044
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA186238
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180820
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.