A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040

Neoplasia. 2005 Apr;7(4):336-47. doi: 10.1593/neo.04532.


PD184352/CI-1040 is a potent and selective MEK1/2 inhibitor that represents the first MEK-targeted agent to enter clinical trials. Here, we report the development and molecular characterization of CI-1040 resistance in the murine colon 26 (C26) carcinoma cell line. The growth rate of the resistant line (C26/CI-1040r) in the presence of 2 microM CI-1040 is comparable to that of parental C26 cells in the absence of CI-1040. C26/CI-1040r cells are approximately 100-fold more resistant than the parental line to CI-1040 inhibition in soft agar and are less sensitive to the induction of apoptosis that normally occurs in response to CI-1040 treatment. K-ras expression is significantly elevated in C26/CI-1040r cells. We confirmed a causative role for K-ras in conferring resistance to CI-1040 by transfecting K-ras into parental C26 cells, whereupon an elevation in the levels of phosphorylated ERK1/2 was observed in addition to resistance to CI-1040. Furthermore, an in vivo-derived MEK inhibitor-resistant line also shows increased K-ras expression. Our data suggest that increasing activated K-ras expression represents one potential mechanism by which tumor cells that initially are responsive to blockade of the MAP kinase pathway can overcome their sensitivity to MEK inhibition.

MeSH terms

  • Agar / chemistry
  • Animals
  • Apoptosis
  • Benzamides / pharmacology*
  • Cell Cycle
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology*
  • Epidermal Growth Factor / metabolism
  • Immunoblotting
  • Immunoprecipitation
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Proto-Oncogene Proteins p21(ras) / physiology*
  • RNA / metabolism
  • RNA, Complementary / metabolism
  • Thymidine / chemistry
  • Time Factors
  • Transfection
  • Up-Regulation


  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Benzamides
  • Enzyme Inhibitors
  • RNA, Complementary
  • Epidermal Growth Factor
  • RNA
  • Agar
  • MAP Kinase Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)
  • Thymidine