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

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posted on 22.11.2019 by Elke Burgermeister, Francesca Battaglin, Fagr Eladly, Wen Wu, Frank Herweck, Nadine Schulte, Johannes Betge, Nicolai Härtel, Jakob N. Kather, Cleo-Aron Weis, Timo Gaiser, Alexander Marx, Christel Weiss, Ralf Hofheinz, Ian S. Miller, Fotios Loupakis, Heinz-Josef Lenz, Annette T. Byrne, Matthias P. Ebert

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

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]).

Funding

DeutscheKrebshilfe (#108287 and #111086). “Studienstiftung des deutschen Volke”. TranslationalPhysician Scientist (TraPS) Program of the Medical Faculty Mannheim of the Heidelberg University. Chinese Scholarship Council (#201408080116). State of Baden-Württemberg for “Center of Geriatric Biology and Oncology (ZOBEL) – Perspektivförderung” and “Biology of Frailty - Sonderlinie Medizin”. European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]). European Commission Horizon 2020 Programme (Contract No. 754923 [COLOSSUS]). Science Foundation Ireland under grant 13/CDA/2183“Coloforetell”. National Cancer Institute (grant number P30CA014089), the Gloria Borges WunderGlo Foundation-The Wunder Project, the Dhont Family Foundation, the San Pedro Peninsula Cancer Guild, the Daniel Butler Research Fund.

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The original article is available at sciencedirect.com

Published Citation

Burgermeister E, Battaglin F, Eladly F, Wu W, Herweck F, Schulte N, Betge J, Härtel N, Kather JN, Weis CA, Gaiser T, Marx A, Weiss C, Hofheinz R, Miller IS, Loupakis F, Lenz HJ, Byrne AT, Ebert MP. Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A. EBioMedicine. 2019;45:139-154.

Publication Date

01/07/2019

Publisher

Elsevier

PubMed ID

31300350

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