Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE
    • Publication Information:
      Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
      Original Publication: London, Lewis.
    • Subject Terms:
      Class I Phosphatidylinositol 3-Kinases/*genetics ; Colonic Neoplasms/*drug therapy ; Colonic Neoplasms/*genetics ; MAP Kinase Kinase 1/*antagonists & inhibitors ; MAP Kinase Kinase 3/*antagonists & inhibitors ; Protein Kinase Inhibitors/*pharmacology ; Proto-Oncogene Proteins p21(ras)/*genetics ; beta Catenin/*metabolism; Acetamides/pharmacology ; Animals ; Biomarkers, Pharmacological/metabolism ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Colonic Neoplasms/metabolism ; Drug Resistance, Viral ; Humans ; MAP Kinase Kinase 1/metabolism ; MAP Kinase Kinase 3/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors ; Proto-Oncogene Proteins p21(ras)/metabolism ; Pyrimidinones/pharmacology ; Xenograft Model Antitumor Assays ; beta Catenin/antagonists & inhibitors
    • Abstract:
      Background: Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients.
      Methods: We investigated a biomarker of response for MEK inhibition in KRAS mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in PIK3CA wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo.
      Results: We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-catenin in PIK3CA wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing PIK3CA wt.
      Conclusions: We propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance.
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    • Accession Number:
      0 (Acetamides)
      0 (Biomarkers, Pharmacological)
      0 (Biomarkers, Tumor)
      0 (CTNNB1 protein, human)
      0 (KRAS protein, human)
      0 (N-(cyclopropylmethyl)-2-(4-(4-methoxybenzoyl)piperidin-1-yl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano(4,3-d)pyrimidin-2-yl)methyl)acetamide)
      0 (Protein Kinase Inhibitors)
      0 (Pyrimidinones)
      0 (beta Catenin)
      EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
      EC 2.7.1.137 (PIK3CA protein, human)
      EC 2.7.12.2 (MAP Kinase Kinase 1)
      EC 2.7.12.2 (MAP Kinase Kinase 3)
      EC 2.7.12.2 (MAP2K1 protein, human)
      EC 2.7.12.2 (MAP2K3 protein, human)
      EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
    • Publication Date:
      Date Created: 20190405 Date Completed: 20200228 Latest Revision: 20210109
    • Publication Date:
      20231215
    • Accession Number:
      PMC6734664
    • Accession Number:
      10.1038/s41416-019-0434-5
    • Accession Number:
      30944457