Mutant ros expression in human cancer

Abstract

The invention provides the identification of the presence of mutant ROS protein in human cancer. In some embodiments, the mutant ROS are FIG-ROS fusion proteins comprising part of the FIG protein fused to the kinase domain of the ROS kinase. In some embodiments, the mutant ROS is the overexpression of wild-type ROS in cancerous tissues (or tissues suspected of being cancerous) where, in normal tissue of that same tissue type, ROS is not expressed or is expressed at lower levels. The mutant ROS proteins of the invention are anticipated to drive the proliferation and survival of a subgroup of human cancers, particularly in cancers of the liver (including bile duct), pancreas, kidney, and testes. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant ROS polypeptides (e.g., a FIG-ROS(S) fusion polypeptide), probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The identification of the mutant ROS polypeptides enables new methods for determining the presence of these mutant ROS 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.

What is claimed is: 
     
         1 . A method comprising administering a therapeutically effective amount of a ROS inhibitor to a patient having a cancer that exhibits a rearrangement involving the ROS gene, thereby treating the cancer, wherein the ROS inhibitor is selected from NVP-TAE684 and PF-02341066. 
     
     
         2 . A method comprising administering a therapeutically effective amount of a ROS inhibitor to a patient identified as having a cancer that exhibits a rearrangement involving the ROS gene, thereby treating the cancer, wherein the ROS inhibitor is selected from NVP-TAE684 and PF-02341066. 
     
     
         3 . A method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a ROS inhibitor, wherein the cancer is characterized by a rearrangement involving the ROS gene, and wherein the ROS inhibitor is selected from NVP-TAE684 and PF-02341066. (p. 2). 
     
     
         4 . A method comprising contacting a cell that exhibits a rearrangement involving the ROS gene with a ROS inhibitor, thereby inhibiting proliferation of the cell, wherein the ROS inhibitor is selected from NVP-TAE684 and PF-02341066. 
     
     
         5 . A method comprising contacting a polypeptide comprising a ROS kinase domain with a ROS inhibitor, thereby inhibiting kinase activity of the polypeptide, wherein the ROS inhibitor is selected from NVP-TAE684 and PF-02341066. 
     
     
         6 . A method comprising administering a therapeutically effective amount of a ROS inhibitor to a patient having a liver cancer that exhibits a rearrangement involving the ROS gene, thereby treating the liver cancer. 
     
     
         7 . A method comprising administering a therapeutically effective amount of a ROS inhibitor to a patient identified as having a liver cancer that exhibits a rearrangement involving the ROS gene, thereby treating the liver cancer. 
     
     
         8 . A method of treating liver cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a ROS inhibitor, wherein the liver cancer is characterized by a rearrangement involving the ROS gene. 
     
     
         9 . A method comprising contacting a liver cancer cell that exhibits a rearrangement involving the ROS gene with a ROS inhibitor, thereby inhibiting proliferation of the cell. 
     
     
         10 . A method comprising administering a therapeutically effective amount of a ROS inhibitor to a patient having a liver cancer that expresses a FIG-ROS polypeptide, thereby treating the cancer. 
     
     
         11 . A method comprising administering a therapeutically effective amount of a ROS inhibitor to a patient identified as having a liver cancer that expresses a FIG-ROS polypeptide, thereby treating the cancer. 
     
     
         12 . A method of treating a liver cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a ROS inhibitor, wherein the liver cancer is characterized by a expression of a FIG-ROS polypeptide. 
     
     
         13 . A method comprising contacting a liver cell that expresses a FIG-ROS polypeptide with a ROS inhibitor, thereby inhibiting proliferation of the cell.