BRAF Mutations Conferring Resistance to BRAF Inhibitors
AssigneeDana-Farber Cancer Institute, Inc.
InventorsLevi Garraway, Caroline Emery
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Abstract
The present invention relates to methods, compositions and kits concerning resistance to treatment with an anti-cancer agent, specifically an inhibitor of BRAF. In particular embodiments, the invention concerns mutations in a BRAF sequence that confer resistance to a BRAF inhibitor. Identification of such mutations in a BRAF sequence allows the identification and design of second-generation BRAF inhibitors. Methods and kits for detecting the presence of a mutant BRAF sequence in a sample are also provided.
Claims24
An isolated mutant BRAF polypeptide having a BRAF activity, wherein said mutant BRAF polypeptide comprises an amino acid sequence having at least one amino acid substitution as compared to a wild type BRAF polypeptide (SEQ ID NO:
- 2) or a BRAF V600E polypeptide (SEQ ID NO:4), the at least one amino acid substitution conferring resistance to one or more BRAF inhibitors on the mutant BRAF polypeptide.
A method of identifying a BRAF inhibitor that inhibits a mutant BRAF polypeptide having BRAF activity, comprising:
- a) selecting a potential drug using computer-assisted modeling with a three-dimensional crystal or solution structure of a mutant BRAF polypeptide, wherein said mutant BRAF polypeptide comprises an amino acid sequence having at least one amino acid substitution as compared to a wild type BRAF polypeptide or a BRAF V600E polypeptide, the at least one amino acid substitution conferring resistance to one or more BRAF inhibitors on the mutant BRAF polypeptide;
- b) contacting said potential drug with the mutant BRAF polypeptide;
- and
- c) detecting the interaction of said potential drug with the mutant BRAF polypeptide;
- wherein a compound that is capable of interacting with the mutant BRAF polypeptide is identified as a BRAF inhibitor that inhibits a mutant BRAF polypeptide having BRAF activity.
A method of treating a subject having cancer, comprising:
- (a) extracting nucleic acid from cells of the cancer;
- (b) performing a nucleic acid-based assay to analyze a nucleic acid molecule encoding a BRAF poly peptide;
- and
- (c) administering a MEK inhibitor or a BRAF inhibitor that inhibits a mutant BRAF polypeptide having BRAF activity to the subject when the nucleic acid molecule contains nucleotides that alter the identity of an amino acid residue at one or more amino acids of the encoded BRAF polypeptide relative to the amino acid at one or more positions selected from the group consisting of A29, H72, S113, S124, P162, C194, L227, P231, C251, V291, Q329, V483, L485, T521, V528, D587, P655, S657, S683, P686, C696, L697, P722, F738, and C748 of SEQ ID NO:2 or SEQ ID NO:4.
Dependencies are inferred from the claim text.