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EBioMedicine. 2019 Jul;45:139-154. doi: 10.1016/j.ebiom.2019.07.004. Epub 2019 Jul 9.

Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A.

Author information

1
Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address: elke.burgermeister@medma.uni-heidelberg.de.
2
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, CA, United States; Unit of Medical Oncology 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
3
Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
4
Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
5
Institute of Pathology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
6
Department of Medical Statistics, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
7
Department of Medicine III, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
8
Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
9
Unit of Medical Oncology 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
10
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, CA, United States.
11
Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.

Abstract

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:

PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J Apcmin/+; BALB/c nu/nu xenografts) and CRC patients under combination chemotherapy with Beva. BMAL1 single nucleotide gene polymorphisms (SNPs) were analysed by DNA-microarray in clinical samples. BMAL1 functions were studied in human CRC cell lines using colorimetric growth, DNA-binding and reporter assays.

FINDINGS:

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:

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]).

KEYWORDS:

ARNTL; BMAL1; Bevacizumab; Colorectal cancer; REVERBA; VEGFA

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