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Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI

BELOUECHE-BABARI, M ; JAMIN, Y ; LEACH, M. O ; ROBINSON, S. P ; ARUNAN, V ; WALKER-SAMUEL, S ; REVILL, M ; SMITH, P. D ; HALLIDAY, J ; WATERTON, J. C ; BARJAT, H ; WORKMAN, P

British journal of cancer, 2013-09, Vol.109 (6), p.1562-1569 [Periódico revisado por pares]

Basingstoke: Nature Publishing Group

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Título:
Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI
Autor: BELOUECHE-BABARI, M ; JAMIN, Y ; LEACH, M. O ; ROBINSON, S. P ; ARUNAN, V ; WALKER-SAMUEL, S ; REVILL, M ; SMITH, P. D ; HALLIDAY, J ; WATERTON, J. C ; BARJAT, H ; WORKMAN, P
Assuntos: Animals ; Benzimidazoles - pharmacology ; Biological and medical sciences ; Biomarkers ; Cancer therapies ; Cell Line, Tumor ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - enzymology ; Diffusion Magnetic Resonance Imaging - methods ; Female ; Humans ; Magnetic resonance imaging ; MAP Kinase Kinase 1 - antagonists & inhibitors ; MAP Kinase Kinase 2 - antagonists & inhibitors ; Medical sciences ; Melanoma - drug therapy ; Melanoma - enzymology ; Mice ; Mice, Nude ; Molecular Targeted Therapy ; Mutation ; Protein Kinase Inhibitors - pharmacology ; Translational Therapeutics ; Tumors ; Xenograft Model Antitumor Assays
É parte de: British journal of cancer, 2013-09, Vol.109 (6), p.1562-1569
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Present address: UCL Centre for Advanced Biomedical Imaging, Department of Medicine and Institute of Child Health, University College London, London WC1E 6DD, UK.
Descrição: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts. Nude mice bearing human BRAF(V600D) WM266.4 melanoma or BRAF(V600E) Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis. Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls. Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies.
Editor: Basingstoke: Nature Publishing Group
Idioma: Inglês

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Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI

BELOUECHE-BABARI, M ; JAMIN, Y ; LEACH, M. O ; ROBINSON, S. P ; ARUNAN, V ; WALKER-SAMUEL, S ; REVILL, M ; SMITH, P. D ; HALLIDAY, J ; WATERTON, J. C ; BARJAT, H ; WORKMAN, P

Basingstoke: Nature Publishing Group

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