Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A.
ARNTL Transcription Factors
/ genetics
Animals
Bevacizumab
/ administration & dosage
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
/ genetics
Female
Heterografts
Humans
Kaplan-Meier Estimate
Male
Mice
Neovascularization, Pathologic
/ drug therapy
Progression-Free Survival
Promoter Regions, Genetic
/ genetics
Vascular Endothelial Growth Factor A
/ genetics
ARNTL
BMAL1
Bevacizumab
Colorectal cancer
REVERBA
VEGFA
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jul 2019
Jul 2019
Historique:
received:
01
04
2019
revised:
26
06
2019
accepted:
02
07
2019
pubmed:
14
7
2019
medline:
7
1
2020
entrez:
14
7
2019
Statut:
ppublish
Résumé
The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA. PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*p = .0061) and reduced progression-free survival (PFS) [*p = .0223, Hazard Ratio (HR) = 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a - 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines. BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. FUND: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]).
Sections du résumé
BACKGROUND
BACKGROUND
The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA.
METHODS
METHODS
PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J
FINDINGS
RESULTS
In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*p = .0061) and reduced progression-free survival (PFS) [*p = .0223, Hazard Ratio (HR) = 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a - 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines.
INTERPRETATION
CONCLUSIONS
BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. FUND: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]).
Identifiants
pubmed: 31300350
pii: S2352-3964(19)30439-6
doi: 10.1016/j.ebiom.2019.07.004
pmc: PMC6642438
pii:
doi:
Substances chimiques
ARNTL Transcription Factors
0
BMAL1 protein, human
0
Vascular Endothelial Growth Factor A
0
Bevacizumab
2S9ZZM9Q9V
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
139-154Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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