MEK1 mutation conferring resistance to RAF and MEK inhibitors

A method of identifying a subject having melanoma cancer as having a high risk of relapse after treatment with a RAF inhibitor or a MEK inhibitor or as being unresponsive to treatment with a RAF inhibitor or a MEK inhibitor, comprising:

• obtaining a sample from a subject having melanoma cancer;
• obtaining a nucleic acid encoding a MEK1 protein from cells of the melanoma cancer in the sample;
• sequencing the nucleic acid encoding the MEK1 protein from the cells of the melanoma cancer, and detecting the presence of nucleotides that produce a C121S amino acid substitution in the MEK1 protein (SEQ ID NO:
• 4) by comparing the sequence of the nucleic acid encoding the MEK1 protein from the cells of the melanoma cancer to a wild-type human MEK1 nucleic acid sequence (SEQ ID NO:
• 1) encoding wild-type MEK1 protein (SEQ ID NO:
• 2) of SEQ ID NO:
• 1 is mutated to tcn (bold and underlined in the mutant MEK1 nucleic acid sequence) in SEQ ID NO:
• 3 encoding the C121S amino acid substitution (bold and underlined in the mutant MEK1 protein) in SEQ ID NO:
• 4 as compared to the wild-type human MEK1 protein (SEQ ID NO:
• 2), where n in tcn is a, c, g, or t;
• identifying the subject having melanoma cancer as having a high risk of relapse after treatment with a RAF inhibitor or a MEK inhibitor or as being unresponsive to treatment with a RAF inhibitor or a MEK inhibitor when the presence of the mutation of nucleic acid sequence from tgc in the wild-type human MEK1 nucleic acid sequence of SEQ ID NO:
• 1 to tcn in the mutant MEK1 nucleic acid sequence of SEQ ID NO:
• 3 encoding the C121S amino acid substitution in the mutant MEK1 protein (SEQ ID NO:
• 4) as compared to the wild-type human MEK1 protein (SEQ ID NO:
• 2) is detected, where n in tcn is a, c, g, or t;
• and
• treating the subject with a second-generation MEK1 inhibitor which inhibits the activity of the mutant MEK1 protein (SEQ ID NO:
• 4) containing the C121S amino acid substitution.