MEK Mutations Conferring Resistance to MEK Inhibitors

摘要

The present invention relates to methods, compositions and kits concerning resistance to treatment with an anti-cancer agent, specifically an inhibitor of MEK. In particular embodiments, the invention concerns mutations in a MEK sequence that confer resistance to a MEK inhibitor. Identification of such mutations in a MEK sequence allows the identification and design of second-generation MEK inhibitors. Methods and kits for detecting the presence of a mutant MEK sequence in a sample are also provided.

主权项

1. A method of identifying a compound that is useful as a MEK inhibitor that inhibits a mutant MEK polypeptide having MEK activity, comprising:
a) providing a cell comprising a mutant MEK polypeptide having MEK activity, the mutant MEK polypeptide comprising an amino acid sequence having at least one amino acid substitution as compared to a wild type MEK1 polypeptide (SEQ ID NO: 2) or a MEK2 polypeptide (SEQ ID NO:4), the at least one amino acid substitution occurring at one or more amino acid positions selected from the group consisting of Q56, I99, I103, K104, I111, R113, L115, H119, E120, P124, G128, F129, F133, E203, V211, L215, G237, V258, G276, G286, M302, P326, and H399 of SEQ ID NO: 2 or Q60, I103, I107, K108, I115, R117, L119, H123, E124, P128, G132, F133, F137, E207, V215, L219, G241, V262, G280, M310, and P334 of SEQ ID NO: 4; b) contacting the cell with a test compound; and c) determining the effect of the compound on MEK activity or determining the effect of the compound on cell proliferation or cell viability; wherein downmodulation of the MEK activity or reduction in cell proliferation or a reduction in cell viability as compared to a suitable control identifies the compound as a compound that is useful as a MEK inhibitor that inhibits the mutant MEK polypeptide having MEK activity.