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 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 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 i) a subject with breast cancer and ii) an inhibitor of a tyrosine kinase, and b) treating said subject with said inhibitor. 
     
     
         2 . The method of  claim 1 , wherein said tyrosine kinase is Bruton's Tyrosine Kinase. 
     
     
         3 . The method of  claim 1 , wherein said tyrosine kinase is a variant of Bruton's Tyrosine Kinase comprising an amino-terminal extension. 
     
     
         4 . The method of  claim 3 , wherein said extension comprises an additional 34 amino acids. 
     
     
         5 . The method of  claim 1 , wherein said inhibitor is ibrutinib. 
     
     
         6 . A method of treating breast cancer, comprising: a) providing i) a subject with breast cancer and ii) ibrutinib, and b) treating said subject with said ibrutinib. 
     
     
         7 . The method of  claim 6 , wherein said breast cancer comprises Her-2 positive cells. 
     
     
         8 . A method of treating breast cancer, comprising: a) providing i) ibrutinib and ii) a subject with breast cancer, wherein said subject has been treated with Herceptin, and b) treating said subject with said ibrutinib.