Bruton's Tyrosine Kinase as Anti-Cancer Drug Target

Abstract

Receptor protein kinases (RPTKs) transmit extracellular signals across the plasma membrane to cytosolic proteins, stimulating formation of complexes that regulate key cellular functions. Over 5 half of the known tyrosine kinases are implicated in human cancers and are therefore highly promising drug targets. A large-scale loss-of-function analysis of tyrosine kinases using RNA interference in the clinically relevant Erb-B2 positive, BT474 breast cancer cell line showed that Bruton's tyrosine kinase (BTK), a cytosolic, non-receptor tyrosine kinase that has been extensively studied for its role in B cell development, is required, in altered form, for BT474 10 breast cancer survival. This alternative form contains an amino-terminal extension that is also present in tumorigenic breast cells at significantly higher levels than in normal breast cells.

1 . A method of treating cancer, comprising:
 a. providing a subject with breast cancer cells and an inhibitor of a gene encoding a cytoplasmic tyrosine kinase;   b. treating said subject with said inhibitor.   
     
     
         2 . The method of  claim 1 , wherein said cytoplasmic tyrosine kinase is a member of the tec family of cytoplasmic tyrosine kinase. 
     
     
         3 . The method of  claim 2 , wherein said cytoplasmic tyrosine kinase is Bruton's Tyrosine Kinase. 
     
     
         4 . The method of  claim 2 , wherein said cytoplasmic tyrosine kinase is a variant of Bruton's Tyrosine Kinase comprising an amino-terminal extension. 
     
     
         5 . The method of  claim 4 , wherein said extension comprises an additional 34 amino acids. 
     
     
         6 . The method of  claim 1 , wherein said inhibitor comprises an interfering RNA. The method of  claim 6 , wherein treating with said RNA results in reduced profileration of said breast cancer cells. 
     
     
         8 . A method of diagnosing cancer, comprising:
 a. providing cell suspected to be breast cancer cells and a ligand capable of binding to a variant of Bruton's Tyrosine Kinase, said variant comprising an amino-terminal extension;   b. contacting said cells with said ligand under conditions wherein said variant is detected.   
     
     
         9 . The method of  claim 8 , wherein said extension comprises an additional 34 amino acids. 
     
     
         10 . The method of  claim 9 , wherein said ligand binds to a portion of said 34 amino acid extension. 
     
     
         11 . The method of  claim 10 , wherein said ligand comprises an antibody or fragment thereof. 
     
     
         12 . A composition, comprising a variant of Bruton's Tyrosine Kinase comprising an amino-terminal extension. 
     
     
         13 . The compositions of  claim 12 , wherein said extension comprises an additional 34 amino acids. 
     
     
         14 . A ligand-protine complex comprising antibody bound to said variant of  claim 12 . 
     
     
         15 . A kit for use in the method of  claim 8 , the kit comprising a ligand capable of binding to a variant of Bruton's tyrosine Kinase and instructions for its use.