Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma.
Afatinib
/ administration & dosage
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Apoptosis
Brain Neoplasms
/ drug therapy
Cell Proliferation
Drug Resistance, Neoplasm
/ drug effects
ErbB Receptors
/ antagonists & inhibitors
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Glioblastoma
/ drug therapy
Humans
Mice
Mice, Inbred C57BL
Mice, Nude
Temozolomide
/ administration & dosage
Thalidomide
/ administration & dosage
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
EGFR
TNF
adaptive response
glioblastoma
temozolomide
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
17 12 2019
17 12 2019
Historique:
pubmed:
1
8
2019
medline:
19
8
2020
entrez:
1
8
2019
Statut:
ppublish
Résumé
Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.
Sections du résumé
BACKGROUND
Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM.
METHODS
We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ.
RESULTS
The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ.
CONCLUSION
EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.
Identifiants
pubmed: 31363754
pii: 5541686
doi: 10.1093/neuonc/noz127
pmc: PMC6917414
doi:
Substances chimiques
Tumor Necrosis Factor-alpha
0
Afatinib
41UD74L59M
Thalidomide
4Z8R6ORS6L
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1529-1539Subventions
Organisme : NCI NIH HHS
ID : R01 CA194578
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197796
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA202403
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.
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