C-RAF mutants that confer resistance to RAF inhibitors
Nucleic acids and proteins having a mutant C-RAF sequence, and methods of identifying patients having cancer who are likely to benefit from a combination therapy and methods of treatment are provided.
1. A method of treating a subject having cancer, the cancer comprising a mutant C-RAF polypeptide, the method comprising:
(a) extracting nucleic acid from a sample of cells of a cancer of a subject having cancer;
(b) assaying at least a portion of a nucleic acid molecule encoding a C-RAF polypeptide from the sample for the presence of a mutation in a nucleic acid molecule encoding a C-RAF polypeptide that have a 257S>P mutation as compared to a wild type C-RAF polypeptide, thereby identifying the subject when the nucleic acid molecule includes nucleotides that alter the amino acid reside of the encoded C-RAF polypeptide having the 257S>P mutation as compared to a wild type C-RAF polypeptide as a subject having cancer, the cancer comprising a mutant C-RAF polypeptide; and
(c) administering an effective amount of a RAF inhibitor and an effective amount of a MEK inhibitor to the subject having cancer, the cancer comprising a mutant C-RAF polypeptide.
2. The method according to claim 1 , wherein the RAF inhibitor is selected from the group consisting of RAF265, sorafenib, SB590885, PLX 4720, PLX4032, GDC-0879, ZM 336372 and(S)-methyl 1-(4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate.
3. The method according to claim 1 , wherein the MEK inhibitor is selected from the group consisting of CI-1040/PD184352, AZD6244, PD318088, PD98059, PD334581, RDEA119, 6-Methoxy-7-(3-morpholin-4-yl-propoxy)-4-(4-phenoxy-phenylamino)-quinoline-3-carbonitrile and 4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile.
4. The method according to claim 1 , wherein the cancer is selected from the group consisting of melanoma, breast cancer, colorectal cancers, glioma, lung cancer, ovarian cancer, sarcoma and thyroid cancer.
5. The method according to claim 1 , wherein the cancer is a RAF dependent cancer.
6. The method according to claim 1 , wherein the cancer is melanoma.
7. A method of identifying and treating a subject having cancer who is likely to benefit from treatment with a combination therapy with a RAF inhibitor and a second inhibitor, the method comprising:
(a) extracting nucleic acid from a sample of cells of a cancer of the subject;
(b) assaying at least a portion of a nucleic acid molecule encoding a C-RAF polypeptide from the sample;
wherein the presence of one or more nucleotides that alter the identity of an amino acid residue at one or more amino acids of the encoded mutant C-RAF polypeptide relative to the amino acid at one or more positions of the wild type C-RAF polypeptide at the 257S>P position indicates a need to treat the subject with a RAF inhibitor and a second inhibitor; and
(c) administering a RAF inhibitor and a second inhibitor to the subject, wherein the second inhibitor is a MEK inhibitor.
8. The method according to claim 7 , wherein the cancer is melanoma.