Translocation and mutant ros kinase in human non-small cell lung carcinoma

Abstract

In accordance with the invention, a novel gene translocation, (4p15, 6q22), in human non-small cell lung carcinoma (NSCLC) that results in a fusion proteins combining part of Sodium-dependent Phosphate Transporter Isoform NaPi-3b protein (SLC34A2) with Proto-oncogene Tyrosine Protein Kinase ROS Precursor (ROS) kinase has now been identified. The SLC34A2-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.

1 - 2 . (canceled) 
     
     
         3 . A method of treating lung cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a ROS inhibitor, wherein the lung cancer is characterized by a rearrangement involving the ROS gene. 
     
     
         4 . A method comprising contacting a lung cancer cell that exhibits a rearrangement involving the ROS gene with a ROS inhibitor, thereby inhibiting proliferation of the cell. 
     
     
         5 . A method comprising administering a therapeutically effective amount of a ROS inhibitor to a patient having a cancer that expresses an SLC34A2-ROS polypeptide, thereby treating the cancer. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . A method comprising contacting a cell that expresses an SLC34A2-ROS polypeptide with a ROS inhibitor, thereby inhibiting proliferation of the cell. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 3 , wherein said lung cancer is non-small cell lung carcinoma (NSCLC). 
     
     
         11 . The method of  claim 3 , wherein said mammal is a human patient. 
     
     
         12 . The method of  claim 3 , wherein said inhibitor inhibits the activity of ROS kinase in said cancer. 
     
     
         13 . The method of  claim 11 , wherein said patient has been identified as having a lung cancer that exhibits a rearrangement involving the ROS gene prior to the administration of the ROS inhibitor. 
     
     
         14 . The method of  claim 13 , wherein the identification is based on detecting the presence of a ROS gene rearrangement in a biological sample obtained from said patient. 
     
     
         15 . The method of  claim 5 , wherein said lung cancer is NSCLC. 
     
     
         16 . The method of  claim 5 , wherein said mammal is a human patient. 
     
     
         17 . The method of  claim 5 , wherein said inhibitor inhibits the activity of ROS kinase in said cancer. 
     
     
         18 . The method of  claim 16 , wherein said patient has been identified as having a cancer that expresses an SLC34A2-ROS polypeptide prior to the administration of said ROS inhibitor. 
     
     
         19 . The method of  claim 18 , wherein the identification is based on detecting the presence of an SLC34A2-ROS polynucleotide or polypeptide in a biological sample obtained from said patient. 
     
     
         20 . The method of  claim 4 , wherein said lung cancer is NSCLC. 
     
     
         21 . The method of  claim 4 , wherein said lung cancer cell is a lung cancer cell in a human patient. 
     
     
         22 . The method of  claim 4 , wherein said inhibitor inhibits the activity of ROS kinase in said lung cancer cell. 
     
     
         23 . The method of  claim 4 , wherein said cell has been identified as a lung cancer cell that exhibits a rearrangement involving the ROS gene prior to being contacted with the ROS inhibitor. 
     
     
         24 . The method of  claim 8 , wherein said cancer is NSCLC. 
     
     
         25 . The method of  claim 8 , wherein said cancer cell is a cancer cell in a human patient. 
     
     
         26 . The method of  claim 8 , wherein said inhibitor inhibits the activity of ROS kinase in said cancer. 
     
     
         27 . The method of  claim 8 , wherein said cancer cell has been identified as a cancer cell that expresses an SLC34A2-ROS polypeptide prior to being contacted with the ROS inhibitor. 
     
     
         28 . The method of  claim 27 , wherein the identification is based on detecting the presence of an SLC34A2-ROS polynucleotide or polypeptide in said cell.