Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
02 03 2023
02 03 2023
Historique:
received:
30
05
2022
revised:
24
10
2022
accepted:
01
12
2022
pubmed:
23
2
2023
medline:
4
3
2023
entrez:
22
2
2023
Statut:
ppublish
Résumé
Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract. However, the role of HH signaling in intrahepatic CCA (iCCA) has not been completely elucidated. In this study, we addressed the function of the main transducer Smoothened (SMO) and the transcription factors (TFs) GLI1 and GLI2 in iCCA. In addition, we evaluated the potential benefits of the combined inhibition of SMO and the DNA damage kinase WEE1. Transcriptomic analysis of 152 human iCCA samples showed increased expression of GLI1, GLI2, and Patched 1 (PTCH1) in tumor tissues compared with nontumor tissues. Genetic silencing of SMO, GLI1, and GLI2 inhibited the growth, survival, invasiveness, and self-renewal of iCCA cells. Pharmacologic inhibition of SMO reduced iCCA growth and viability in vitro, by inducing double-strand break DNA damage, leading to mitotic arrest and apoptotic cell death. Importantly, SMO inhibition resulted in the activation of the G2-M checkpoint and DNA damage kinase WEE1, increasing the vulnerability to WEE1 inhibition. Hence, the combination of MRT-92 with the WEE1 inhibitor AZD-1775 showed increased antitumor activity in vitro and in iCCA xenografts compared with single treatments. These data indicate that combined inhibition of SMO and WEE1 reduces tumor burden and may represent a strategy for the clinical development of novel therapeutic approaches in iCCA.
Identifiants
pubmed: 36807728
pii: 716668
doi: 10.1158/1535-7163.MCT-22-0379
pmc: PMC9978885
doi:
Substances chimiques
Cell Cycle Proteins
0
Hedgehog Proteins
0
Protein-Tyrosine Kinases
EC 2.7.10.1
Receptors, G-Protein-Coupled
0
Smoothened Receptor
0
WEE1 protein, human
EC 2.7.10.2
Zinc Finger Protein GLI1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
343-356Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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