Methods and compositions for the diagnosis and treatment of cancer resistant to anaplastic lymphoma kinase (alk) kinase inhibitors

An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of:

• a) the nucleotide sequence set forth in SEQ ID NO:5, 7, 9, 11, 13, 15, 17, 19, 21, 25, 27, 29, 31, 98, 100, or 102;
• b) a nucleotide sequence encoding the amino acid sequence set forth in SEQ ID NO:6, 8, 10, 12, 14, 16, 18, 20, 22, 26, 28, 30, 32, 99, 101, or 103;
• c) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:5 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:6, wherein the polynucleotide encodes a polypeptide having a serine residue at the position corresponding to amino acid residue position 1123 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one anaplastic lymphoma kinase (ALK) small-molecule kinase inhibitor;
• d) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:7 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:8, wherein the polynucleotide encodes a polypeptide having an alanine residue at the position corresponding to amino acid residue position 1123 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• e) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:9 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:10, wherein the polynucleotide encodes a polypeptide having a valine residue thereof at the position corresponding to amino acid residue position 1129 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• f) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:11 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:12, wherein the polynucleotide encodes a polypeptide having a lysine residue at the position corresponding to amino acid residue position 1132 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• g) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:13 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:14, wherein the polynucleotide encodes a polypeptide having a methionine residue at the position corresponding to amino acid residue position 1151 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• h) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:15 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:16, wherein the polynucleotide encodes a polypeptide having a tyrosine residue at the position corresponding to amino acid residue position 1156 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• i) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:17 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:18, wherein the polynucleotide encodes a polypeptide having a cysteine residue at the position corresponding to amino acid residue position 1174 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• j) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:19 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:20, wherein the polynucleotide encodes a polypeptide having an isoleucine residue at the position corresponding to amino acid residue position 1174 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• k) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:21 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:22, wherein the polynucleotide encodes a polypeptide having a valine residue at the position corresponding to amino acid residue position 1174 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• l) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:25 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:26, wherein the polynucleotide encodes a polypeptide having an arginine residue at the position corresponding to amino acid residue position 1202 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• m) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:27 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:28, wherein the polynucleotide encodes a polypeptide having an asparagine residue at the position corresponding to amino acid residue position 1203 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• n) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:29 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:30, wherein the polynucleotide encodes a polypeptide having a lysine residue at the position corresponding to amino acid residue position 1210 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• o) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:31 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:32, wherein the polynucleotide encodes a polypeptide having an alanine residue at the position corresponding to amino acid residue position 1269 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• p) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:98 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:99, wherein the polynucleotide encodes a polypeptide having a lysine residue at the position corresponding to amino acid residue position 1406 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• q) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:100 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:101, wherein the polynucleotide encodes a polypeptide having a lysine residue at the position corresponding to amino acid residue position 1408 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor;
• and,
• r) a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:102 or a nucleotide sequence encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO:103, wherein the polynucleotide encodes a polypeptide having a leucine residue at the position corresponding to amino acid residue position 1174 of SEQ ID NO:2, and wherein the polynucleotide encodes a polypeptide having kinase activity that is resistant to at least one ALK small-molecule kinase inhibitor.