Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI |
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Authors: | M Beloueche-Babari Y Jamin V Arunan S Walker-Samuel M Revill P D Smith J Halliday J C Waterton H Barjat P Workman M O Leach S P Robinson |
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Institution: | 1.Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK;2.AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK;3.Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK |
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Abstract: | 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 BRAFV600D WM266.4 melanoma or BRAFV600E 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. |
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Keywords: | MEK biomarker non-invasive imaging diffusion-weighted MRI human tumour xenografts |
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