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|Ref Type||Journal Article|
|Authors||Beloueche-Babari M, Jamin Y, Arunan V, Walker-Samuel S, Revill M, Smith PD, Halliday J, Waterton JC, Barjat H, Workman P, Leach MO, Robinson SP|
|Title||Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI.|
|Journal||British journal of cancer|
|Date||2013 Sep 17|
|Abstract Text||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.|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
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|BRAF V600E||colorectal cancer||sensitive||Selumetinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Selumetinib (AZD6244) decreased tumor growth in a cell line xenograft model of colorectal cancer harboring BRAF V600E (PMID: 23942066).||23942066|