The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors.
Aged
Antineoplastic Agents
/ chemistry
Cell Cycle
/ drug effects
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
DNA Damage
Drug Screening Assays, Antitumor
Female
Humans
Male
Phthalazines
/ chemistry
Poly(ADP-ribose) Polymerase Inhibitors
/ chemistry
Poly(ADP-ribose) Polymerases
/ metabolism
Protein-Tyrosine Kinases
/ antagonists & inhibitors
Tumor Cells, Cultured
Ewing’s sarcoma
PARP inhibitor
PARP1
PARP16
adavosertib
lung cancer
off-target
polypharmacology
proteomics
talazoparib
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
17 02 2022
17 02 2022
Historique:
received:
02
08
2020
revised:
08
04
2021
accepted:
08
07
2021
pubmed:
31
7
2021
medline:
9
3
2022
entrez:
30
7
2021
Statut:
ppublish
Résumé
PARP inhibitors (PARPis) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determine the differential efficacy of multiple clinical PARPis in SCLC cells. Compared with the other PARPis rucaparib, olaparib, and niraparib, talazoparib displays the highest potency across SCLC, including SLFN11-negative cells. Chemical proteomics identifies PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduces cell survival, particularly in combination with PARP1 inhibition. Drug combination screening reveals talazoparib synergy with the WEE1/PLK1 inhibitor adavosertib. Global phosphoproteomics identifies disparate effects on cell-cycle and DNA damage signaling thereby illustrating underlying mechanisms of synergy, which is more pronounced for talazoparib than olaparib. Notably, silencing PARP16 further reduces cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib's overall mechanism of action and constitutes an actionable target in SCLC.
Identifiants
pubmed: 34329582
pii: S2451-9456(21)00348-2
doi: 10.1016/j.chembiol.2021.07.008
pmc: PMC8782927
mid: NIHMS1728850
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Cell Cycle Proteins
0
Phthalazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
talazoparib
9QHX048FRV
PARP16 protein, human
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
Protein-Tyrosine Kinases
EC 2.7.10.1
WEE1 protein, human
EC 2.7.10.2
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
202-214.e7Subventions
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181746
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211447
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.