TRANSLOCATION AND MUTANT ROS KINASE IN HUMAN NON-SMALL CELL LUNG CARCINOMA

摘要

In accordance with the invention, a novel gene translocation, (5q32, 6q22), in human non-small cell lung carcinoma (NSCLC) that results in a fusion proteins combining part of CD74 with Proto-oncogene Tyrosine Protein Kinase ROS Precursor (ROS) kinase has now been identified. The CD74-ROS fusion protein is anticipated to drive the proliferation and survival of a subgroup of NSCLC tumors. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant ROS kinase polypeptides, probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The disclosed identification of the new fusion protein enables new methods for determining the presence of these mutant ROS kinase polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides, which are also provided by the invention.

主权项

1. An isolated polynucleotide comprising a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a nucleotide sequence encoding a CD74-ROS fusion polypeptide comprising the amino acid sequence of SEQ ID NO: 1; (b) a nucleotide sequence encoding a CD74-ROS fusion polypeptide, said nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 2; (c) a nucleotide sequence encoding a CD74-ROS fusion polypeptide comprising the N-terminal amino acid sequence of CD74 (residues 1-208 of SEQ ID NO: 3) and the kinase domain of ROS (residues 1945-2222 of SEQ ID NO: 5); (d) a nucleotide sequence comprising the N-terminal nucleotide sequence of CD74 (residues 1-624 of SEQ ID NO: 4) and the kinase domain nucleotide sequence of ROS (residues 6032-6865 of SEQ ID NO: 6); (e) a nucleotide sequence comprising at least six contiguous nucleotides encompassing the fusion junction (residues 622-627 of SEQ ID NO: 2) of a CD74-ROS fusion polynucleotide; (f) a nucleotide sequence encoding a polypeptide comprising at least six contiguous amino acids encompassing the fusion junction (residues 208-209 of SEQ ID NO: 1) of a CD74-ROS fusion polypeptide; and (g) a nucleotide sequence complementary to any of the nucleotide sequences of (a)-(f).