A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040.
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.
Wang
Yuli
Y
Molecular Sciences and Technologies, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. yuli.wang@pfizer.com
Van Becelaere
Keri
K
Jiang
Ping
P
Przybranowski
Sally
S
Omer
Charles
C
Sebolt-Leopold
Judith
J
D000362:Agar / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism / Q000502:physiology*; D012313:RNA / Q000378:metabolism; D018075:RNA, Complementary / Q000378:metabolism; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D004791:Enzyme Inhibitors; D018075:RNA, Complementary; D004815:Epidermal Growth Factor; D012313:RNA; D000362:Agar; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D013936:Thymidine