MET FUSIONS
The invention provides MET gene fusions. MET fusion proteins, and fragments of those genes and polypeptides. The invention further provides methods of diagnosing and treating diseases or disorders associated with MET fusions, such as conditions mediated by aberrant MET expression or activity or overexpression of MET.
1 - 96 . (canceled)
97 . A method for detecting in a patient a MET fusion that results in aberrant activity or expression of MET or overexpression of MET, wherein the MET fusion is a BAIAP2L1:MET, C8orf34:MET, PTPRZ1:MET, OXR1:MET, KIF5B:MET, or TFG:MET fusion, said method comprising:
a) contacting a biological sample from the patient with a reagent selected from:
i) an antibody that specifically binds to a MET fusion protein, but does not specifically bind to wild-type MET, BAIAP2L1, C8orf34, PTPRZ1, OXR1, KIF5B, or TFG; or
ii) an oligonucleotide that hybridizes to the fusion junction of a MET gene fusion; and
b) detecting binding between the MET fusion and the reagent.
98 . The method of claim 97 , wherein the MET fusion is:
a) a gene fusion that comprises:
i) SEQ ID NO:1, 3, 5, 7, 9, 11, or 13, or
ii) a portion of SEQ ID NO 1, 3, 5, 7, 9, 11, or 13, wherein the portion comprises a fusion junction between MET and its fusion partner and the gene fusion encodes a polypeptide having MET kinase activity, or
b) a fusion protein that comprises:
i) SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, or
ii) a portion of SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, wherein the portion comprises a fusion junction between MET and its fusion partner and the fusion protein has MET kinase activity.
99 . The method of claim 98 , wherein the reagent is an oligonucleotide that hybridizes under stringent conditions to:
a) a fragment of SEQ ID NO:1 comprising nucleotides 951-960 of SEQ ID NO:1;
b) a fragment of SEQ ID NO:3 comprising nucleotides 471-480 of SEQ ID NO:3;
c) a fragment of SEQ ID NO:5 comprising nucleotides 54-63 of SEQ ID NO:5;
d) a fragment of SEQ ID NO:7 comprising nucleotides 62-71 of SEQ ID NO:7;
e) a fragment of SEQ ID NO:9 comprising nucleotides 1952-1961 of SEQ ID NO:9;
f) a fragment of SEQ ID NO:11 comprising nucleotides 2757-2766 of SEQ ID NO:11;
g) a fragment of SEQ ID NO:13 comprising nucleotides 576-585 of SEQ ID NO:13; or
h) a complementary oligonucleotide of any one of a)-g).
100 . The method of claim 98 , wherein the reagent is an antibody that specifically binds to:
a) a fragment of SEQ ID NO:2 comprising amino acids 314-323 of SEQ ID NO:2;
b) a fragment of SEQ ID NO:4 comprising amino acids 155-164 of SEQ ID NO:4;
c) a fragment of SEQ ID NO:6 comprising amino acids 16-30 of SEQ ID NO:6; or
d) a fragment of SEQ ID NO:8 comprising amino acids 17-26 of SEQ ID NO:8;
e) a fragment of SEQ ID NO:10 comprising amino acids 648-657 of SEQ ID NO:10;
f) a fragment of SEQ ID NO:12 comprising amino acids 916-925 of SEQ ID NO:12; or
g) a fragment of SEQ ID NO:14 comprising amino acids 190-199 of SEQ ID NO:14.
101 . The method of claim 98 , wherein the patient is suffering from or susceptible to a cancer.
102 . The method of claim 101 , wherein the cancer is chosen from papillary renal cell carcinoma, brain lower grade glioma, hepatocellular carcinoma, lung adenocarcinoma, and thyroid carcinoma.
103 . A method of treating a patient in which a MET fusion selected from BAIAP2L1:MET, C8orf34:MET, PTPRZ1:MET, OXR1:MET, KIF5B:MET, and TFG:MET has been detected, said method comprising administering to the patient a therapeutically effective amount of a compound that inhibits MET activity or the activity or expression of the MET fusion, wherein the MET fusion has been detected in the patient by a method comprising:
a) contacting a biological sample from the patient with a reagent selected from:
i) an antibody that specifically binds to a MET fusion protein, but does not specifically bind to wild-type MET, BAIAP2L1, C8orf34, PTPRZ1, OXR1, KIF5B, or TFG; or
ii) an oligonucleotide that hybridizes to the fusion junction of a MET gene fusion; and
b) detecting binding between the MET fusion and the reagent.
104 . The method of claim 103 , wherein the MET fusion is:
a) a gene fusion that comprises:
i) SEQ ID NO:1, 3, 5, 7, 9, 11, or 13, or
ii) a portion of SEQ ID NO 1, 3, 5, 7, 9, 11, or 13, wherein the portion comprises a fusion junction between MET and its fusion partner and the gene fusion encodes a polypeptide having MET kinase activity, or
b) a fusion protein that comprises:
i) SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, or
ii) a portion of SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, wherein the portion comprises a fusion junction between MET and its fusion partner and the fusion protein has MET kinase activity.
105 . The method of claim 103 , wherein the reagent is an oligonucleotide that hybridizes under stringent conditions to:
a) a fragment of SEQ ID NO:1 comprising nucleotides 951-960 of SEQ ID NO:1;
b) a fragment of SEQ ID NO:3 comprising nucleotides 471-480 of SEQ ID NO:3;
c) a fragment of SEQ ID NO:5 comprising nucleotides 54-63 of SEQ ID NO:5;
d) a fragment of SEQ ID NO:7 comprising nucleotides 62-71 of SEQ ID NO:7;
e) a fragment of SEQ ID NO:9 comprising nucleotides 1952-1961 of SEQ ID NO:9;
f) a fragment of SEQ ID NO:11 comprising nucleotides 2757-2766 of SEQ ID NO:11;
g) a fragment of SEQ ID NO:13 comprising nucleotides 576-585 of SEQ ID NO:13; or
h) a complementary oligonucleotide of any one of a)-g).
106 . The method of claim 103 , wherein the reagent is an antibody specifically binds to:
a) a fragment of SEQ ID NO:2 comprising amino acids 314-323 of SEQ ID NO:2;
b) a fragment of SEQ ID NO:4 comprising amino acids 155-164 of SEQ ID NO:4;
c) a fragment of SEQ ID NO:6 comprising amino acids 16-30 of SEQ ID NO:6; or
d) a fragment of SEQ ID NO:8 comprising amino acids 17-26 of SEQ ID NO:8;
e) a fragment of SEQ ID NO:10 comprising amino acids 648-657 of SEQ ID NO:10;
f) a fragment of SEQ ID NO:12 comprising amino acids 916-925 of SEQ ID NO:12; or
g) a fragment of SEQ ID NO:14 comprising amino acids 190-199 of SEQ ID NO:14.
107 . The method of claim 103 , wherein the patient is suffering from or susceptible to a cancer.
108 . The method of claim 107 , wherein the cancer is chosen from papillary renal cell carcinoma, brain lower grade glioma, hepatocellular carcinoma, lung adenocarcinoma, and thyroid carcinoma.
109 . A method for diagnosing cancer in a patient comprising:
a) contacting a biological sample from the patient with a reagent selected from:
i) an antibody that specifically binds to a MET fusion protein selected from BAIAP2L1:MET, C8orf34:MET, PTPRZ1:MET, OXR1:MET, KIF5B:MET, and TFG:MET, but does not specifically bind to wild-type MET, BAIAP2L1, C8orf34, PTPRZ1, OXR1, KIF5B, or TFG; or
ii) an oligonucleotide that hybridizes to the fusion junction of a MET gene fusion selected from BAIAP2L1:MET, C8orf34:MET, PTPRZ1:MET, OXR1:MET, KIF5B:MET, and TFG:MET; and
b) diagnosing the patient with cancer when the presence of the MET fusion protein or MET gene fusion in the biological sample is detected.
110 . A molecule capable of specifically binding to a MET fusion, wherein the fusion results in aberrant activity or expression of MET or overexpression MET, wherein the molecule is selected from:
a) an antibody that specifically binds to a MET fusion protein selected from BAIAP2L1:MET, C8orf34:MET, PTPRZ1:MET, OXR1:MET, KIF5B:MET, and TFG:MET, but does not specifically bind to wild-type MET, BAIAP2L1, C8orf34, PTPRZ1, OXR1, KIF5B, or TFG; or
b) an oligonucleotide that hybridizes to the fusion junction of a MET gene fusion selected from BAIAP2L1:MET, C8orf34:MET, PTPRZ1:MET, OXR1:MET, KIF5B:MET, and TFG:MET.
111 . The molecule of claim 110 , wherein:
a) the gene fusion that the molecule specifically binds to comprises:
i) SEQ ID NO:1, 3, 5, 7, 9, 11, or 13, or
ii) a portion of SEQ ID NO 1, 3, 5, 7, 9, 11, or 13, wherein the portion comprises a fusion junction between MET and its fusion partner and the gene fusion encodes a polypeptide having MET kinase activity, or
b) the fusion protein that the molecule specifically binds to comprises:
i) SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, or
ii) a portion of SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, wherein the portion comprises a fusion junction between MET and its fusion partner and the fusion protein has MET kinase activity.
112 . The molecule of claim 110 , wherein the molecule is an oligonucleotide that hybridizes under stringent conditions to:
a) a fragment of SEQ ID NO:1 comprising nucleotides 951-960 of SEQ ID NO:1;
b) a fragment of SEQ ID NO:3 comprising nucleotides 471-480 of SEQ ID NO:3;
c) a fragment of SEQ ID NO:5 comprising nucleotides 54-63 of SEQ ID NO:5;
d) a fragment of SEQ ID NO:7 comprising nucleotides 62-71 of SEQ ID NO:7;
e) a fragment of SEQ ID NO:9 comprising nucleotides 1952-1961 of SEQ ID NO:9;
f) a fragment of SEQ ID NO: 11 comprising nucleotides 2757-2766 of SEQ ID NO:11;
g) a fragment of SEQ ID NO:13 comprising nucleotides 576-585 of SEQ ID NO:13; or
h) a complementary oligonucleotide of any one of a)-g).
113 . The molecule of claim 110 , wherein the molecule is an antibody specifically binds to:
a) a fragment of SEQ ID NO:2 comprising amino acids 314-323 of SEQ ID NO:2;
b) a fragment of SEQ ID NO:4 comprising amino acids 155-164 of SEQ ID NO:4;
c) a fragment of SEQ ID NO:6 comprising amino acids 16-30 of SEQ ID NO:6; or
d) a fragment of SEQ ID NO:8 comprising amino acids 17-26 of SEQ ID NO:8;
e) a fragment of SEQ ID NO: 10 comprising amino acids 648-657 of SEQ ID NO:10;
f) a fragment of SEQ ID NO:12 comprising amino acids 916-925 of SEQ ID NO:12; or
g) a fragment of SEQ ID NO:14 comprising amino acids 190-199 of SEQ ID NO:14.