Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma.
Animals
Carcinoma, Mucoepidermoid
/ drug therapy
Cell Proliferation
/ drug effects
ErbB Receptors
/ antagonists & inhibitors
Erlotinib Hydrochloride
/ pharmacology
Heterografts
Humans
Mice
Molecular Targeted Therapy
Neoplastic Stem Cells
/ drug effects
Oncogene Proteins, Fusion
/ genetics
Receptors, Notch
/ antagonists & inhibitors
Salivary Gland Neoplasms
/ drug therapy
Signal Transduction
/ drug effects
Trans-Activators
/ genetics
Transcription Factors
/ genetics
Translocation, Genetic
/ genetics
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
21 01 2021
21 01 2021
Historique:
received:
13
03
2020
accepted:
12
10
2020
revised:
29
09
2020
entrez:
21
1
2021
pubmed:
22
1
2021
medline:
5
3
2022
Statut:
epublish
Résumé
Mucoepidermoid carcinoma (MEC) is the most common type of salivary gland cancers and patients with advanced, metastatic, and recurrent MECs have limited therapeutic options and poor treatment outcomes. MEC is commonly associated with a chromosomal translocation t(11;19) (q14-21;p12-13) that encodes the CRTC1-MAML2 oncogenic fusion. The CRTC1-MAML2 fusion is required for MEC growth in part through inducing autocrine AREG-EGFR signaling. Growing evidence suggests that MEC malignancy is maintained by cancer stem-like cells. In this study, we aimed to determine critical signaling for maintaining MEC stem-like cells and the effect of combined targeting of stem cell signaling and CRTC1-MAML2-induced EGFR signaling on blocking MEC growth. First, we evaluated the significance of Notch signaling in regulating MEC stem-like cells. Aberrantly activated Notch signaling was detected in human fusion-positive MEC cells. The inhibition of Notch signaling with genetic or pharmacological inhibitors reduced oncosphere formation and ALDH-bright population in vitro and blocked the growth of MEC xenografts in vivo. Next, we investigated the effect of co-targeting Notch signaling and EGFR signaling, and observed enhanced inhibition on MEC growth in vivo. Collectively, this study identified a critical role of Notch signaling in maintaining MEC stem-like cells and tumor growth, and revealed a novel approach of co-targeting Notch and EGFR signaling as a potential effective anti-MEC treatment.
Identifiants
pubmed: 33473104
doi: 10.1038/s41392-020-00388-0
pii: 10.1038/s41392-020-00388-0
pmc: PMC7817832
doi:
Substances chimiques
CRTC1 protein, human
0
MAML2 protein, human
0
Oncogene Proteins, Fusion
0
Receptors, Notch
0
Trans-Activators
0
Transcription Factors
0
Erlotinib Hydrochloride
DA87705X9K
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
27Subventions
Organisme : NCI NIH HHS
ID : R01 CA234351
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE023641
Pays : United States
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