Combine MEK inhibition with PI3K/mTOR inhibition exert inhibitory tumor growth effect on KRAS and PIK3CA mutation CRC xenografts due to reduced expression of VEGF and matrix metallopeptidase-9

Tumour Biol. 2015 Feb;36(2):1091-7. doi: 10.1007/s13277-014-2667-5. Epub 2014 Oct 19.


Although epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab are used widely to treat KRAS wild-type metastatic colorectal cancer (mCRC), patients become resistant by various mechanisms, including KRAS, BRAF, and PIK3CA mutations, thereafter relapsing. AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we investigated the mechanisms of AZD6244 alone or with BEZ235, an orally available potent inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in a KRAS and PIK3CA mutation CRC xenograft model. HCT116 (KRAS (G13D) , PIK3CA (H1047R) mutant) cells were subcutaneously injected into the nude mice. Mice were randomly assigned to treatment with vehicle, cetuximab, AZD6244, BEZ235, or AZD6244 plus BEZ235, for up to 3 weeks; then, all mice were sacrificed, and tumor tissues were subjected to Western blot analysis and immunohistochemical staining. AZD6244 or BEZ235 slightly inhibit tumor growth of HCT116 xenografts, and the combination treatment markedly enhanced their antitumor effects. However, cetuximab had no effect on tumor growth. Western blot analysis and immunohistochemical staining revealed that treatment with AZD6244 or BEZ235 could significantly reduce the phosphorylation level of ERK1/2 or AKT in HCT116 tumor tissues. More interesting, the antiangiogenic effects were substantially enhanced when the agents were combined which may due to the reduced expression of VEGF and matrix metallopeptidase-9 (MMP-9) in tumor tissues. These results suggest that the combination of a selective MEK inhibitor and a PI3K/mTOR inhibitor was effective in CRC harboring with KRAS and PIK3CA mutations. The mechanisms of synergistic antitumor effects may be due to antiangiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Benzimidazoles / administration & dosage
  • Cetuximab
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm / genetics
  • HCT116 Cells
  • Humans
  • Imidazoles / administration & dosage
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / genetics
  • Matrix Metalloproteinase 9 / biosynthesis*
  • Mice
  • Phosphatidylinositol 3-Kinases / genetics*
  • Protein Kinase Inhibitors / administration & dosage
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Quinolines / administration & dosage
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics*
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics*


  • AZD 6244
  • Antibodies, Monoclonal, Humanized
  • Benzimidazoles
  • Imidazoles
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Quinolines
  • Vascular Endothelial Growth Factor A
  • MTOR protein, human
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • TOR Serine-Threonine Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Matrix Metalloproteinase 9
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab
  • dactolisib