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Ex vivo treatment of patient biopsies as a novel method to assess colorectal tumour response to the MEK1/2 inhibitor, Selumetinib

Lookup NU author(s): Professor Steve Wedge

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 The Author(s). Although an array of new therapeutics has emerged for the treatment of colorectal cancer, their use is significantly impacted by variability in patient response. Better pre-clinical models could substantially improve efficacy as it may allow stratification of patients into the correct treatment regime. Here we explore acute, ex vivo treatment of fresh, surgically resected human colorectal tumour biopsies as a novel pre-clinical model for identifying patient response to specific therapeutics. The MEK1/2 inhibitor, Selumetinib (AZD6244, ARRY-142886) was used as a tool compound. Firstly, we established an acute treatment protocol and demonstrated this protocol could differentiate phenotypic and pharmacodynamic responses to Selumetinib (0-3uM). We then used the protocol to evaluate Selumetinib response in tumours from 23 colon cancer patients. These studies revealed that the agent inhibited pERK1/2 phosphorylation in all tumours, caused a significant decrease in proliferation in 5/23 (22%) tumours, and that KRAS/BRAF mutant tumours were particularly sensitive to the anti-proliferative effects of the agent. These data are consistent with data from clinical trials of Selumetinib, suggesting that acute treatment of small tumour biopsies is worthy of further exploration as a pre-clinical model to evaluate colorectal cancer response to novel therapies.


Publication metadata

Author(s): Novo SM, Wedge SR, Stark LA

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2017

Volume: 7

Issue: 1

Online publication date: 20/09/2017

Acceptance date: 06/09/2017

Date deposited: 20/10/2017

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41598-017-12222-9

DOI: 10.1038/s41598-017-12222-9


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