Protein kinase inhibitor

From Dog

Protein kinase inhibitors are gene therapy drugs which bind and stabilize the inactivated form of the receptor tyrosine kinases which leads to inhibition of phosphorylation and downstream KIT signaling activation.

The receptor tyrosine kinase KIT is expressed by a number of canine neoplasms including hematopoietic progenitor cells, germ cells, interstitial cells of Cajal, melanocytes, and mast cells, where it has been associated with cell survival, proliferation, and differentiation[1].

In addition to these functions, in mast cells, KIT has been shown to be important for fibronectin adhesion, chemotaxis, and degranulation[2].

These drugs have revolutionized the treatment of many previous untreatable forms of canine cancer including gastrointestinal stromal tumor, mast cell tumor, thyroid carcinoma and anal sac adenocarcinoma[3].

The use of these drugs is limited in some situations where their limited ability to bind to inactivated form of the tyrosine kinase results in drug resistance by the neoplasm.

Drugs include:


  1. Nocka K et al (1989) Expression of c-kit gene products in known cellular targets of W mutations in normal and W mutant mice—evidence for an impaired c-kit kinase in mutant mice. Genes Dev 3:816–826
  2. Nocka K et al (1990) Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors. EMBO J 9:3287–3294
  3. London CA et al (2009) Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Can Res 15(11):3856-3865