Generation and characterization of MEK and ERK inhibitors- resistant non-small-cells-lung-cancer (NSCLC) cells

摘要: The RAS/RAF/MEK/ERK pathway is one of the most downregulated in cancer. Inhibitors RAF and MEK have established clinical use while ERK inhibitors recently faced clinic. We aimed to generate resistant cell lines which could be helpful for defining new combinations able overcome resistance. human NSCLC line NCI-H727, sensitive both inhibitors, was treated with increasing concentrations MEK162 (as inhibitor) or SCH772984 as inhibitor. we successfully obtained a subline (H727/MEK, after 40 passages) well an (H727/SCH, 18 passages). two sublines H727/MEK H727/SCH were cross-resistant respectively, but not inhibitors. maintained responsiveness parallel PI3K/akt/mTOR agents different mechanism action. Mechanistically, treatment cells induce similar inhibition phosphorylation, only parental drugs downregulation S6 RSK phosphorylation. these represent important tool further studies on mechanisms resistance ways it.