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

被引：19

作者：

Beloueche-Babari, M. ^{[1
]}

Jamin, Y. ^{[1
]}

Arunan, V. ^{[1
]}

Walker-Samuel, S. ^{[1
]}

Revill, M. ^{[2
]}

Smith, P. D. ^{[2
]}

Halliday, J. ^{[2
]}

Waterton, J. C. ^{[2
]}

Barjat, H. ^{[2
]}

Workman, P. ^{[3
]}

Leach, M. O. ^{[1
]}

Robinson, S. P. ^{[1
]}

机构：

[1] Inst Canc Res & Royal Marsden NHS Fdn Trust, Div Radiotherapy & Imaging, Canc Res UK & EPSRC Canc Imaging Ctr, Sutton SM2 5PT, Surrey, England

[2] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England

[3] Inst Canc Res, Div Canc Therapeut, Canc Res UK Canc Therapeut Unit, Sutton SM2 5NG, Surrey, England

来源：

BRITISH JOURNAL OF CANCER | 2013年 / 109卷 / 06期

基金：

英国工程与自然科学研究理事会;

关键词：

MEK; biomarker; non-invasive imaging; diffusion-weighted MRI; human tumour xenografts; KINASE KINASE-1/2 INHIBITOR; ONCOLOGY DRUG DEVELOPMENT; EARLY CLINICAL-TRIALS; IMAGING BIOMARKERS; ANTITUMOR-ACTIVITY; IMPROVED SURVIVAL; BRAF MUTATIONS; MELANOMA; CANCER; THERAPY;

D O I：

10.1038/bjc.2013.456

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

引用

页码：1562 / 1569

页数：8

共 48 条

[1] Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers [J].