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

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  • Author(s): Novo SM;Novo SM; Wedge SR; Wedge SR; Stark LA; Stark LA
  • Source:
    Scientific reports [Sci Rep] 2017 Sep 20; Vol. 7 (1), pp. 12020. Date of Electronic Publication: 2017 Sep 20.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • Subject Terms:
      Benzimidazoles/*therapeutic use ; Colon/*drug effects ; Colorectal Neoplasms/*drug therapy ; MAP Kinase Kinase 1/*antagonists & inhibitors ; MAP Kinase Kinase 2/*antagonists & inhibitors ; Rectum/*drug effects; Adult ; Aged ; Aged, 80 and over ; Benzimidazoles/pharmacology ; Biopsy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Colon/metabolism ; Colon/pathology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Female ; HCT116 Cells ; Humans ; MAP Kinase Kinase 1/metabolism ; MAP Kinase Kinase 2/metabolism ; Male ; Middle Aged ; Mutation ; Rectum/metabolism ; Rectum/pathology ; ras Proteins/genetics
    • Abstract:
      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.
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    • Grant Information:
      10-0158 United Kingdom AICR_ Worldwide Cancer Research; ETM/154 United Kingdom CSO_ Chief Scientist Office; MR/J001481/1 United Kingdom MRC_ Medical Research Council
    • Accession Number:
      0 (AZD 6244)
      0 (Benzimidazoles)
      EC 2.7.12.2 (MAP Kinase Kinase 1)
      EC 2.7.12.2 (MAP Kinase Kinase 2)
      EC 3.6.5.2 (ras Proteins)
    • Publication Date:
      Date Created: 20170922 Date Completed: 20190716 Latest Revision: 20220129
    • Publication Date:
      20221213
    • Accession Number:
      PMC5607258
    • Accession Number:
      10.1038/s41598-017-12222-9
    • Accession Number:
      28931905